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1
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Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options. Cells 2022; 11:cells11172620. [PMID: 36078027 PMCID: PMC9454765 DOI: 10.3390/cells11172620] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/03/2022] [Accepted: 08/19/2022] [Indexed: 12/15/2022] Open
Abstract
Alcohol and several therapeutic drugs, including acetaminophen, are metabolized by cytochrome P450 2E1 (CYP2E1) into toxic compounds. At low levels, these compounds are not detrimental, but higher sustained levels of these compounds can lead to life-long problems such as cytotoxicity, organ damage, and cancer. Furthermore, CYP2E1 can facilitate or enhance the effects of alcohol-drug and drug-drug interactions. In this review, we discuss the role of CYP2E1 in the metabolism of alcohol and drugs (with emphasis on acetaminophen), mediating injury/toxicities, and drug-drug/alcohol-drug interactions. Next, we discuss various compounds and various nutraceuticals that can reduce or prevent alcohol/drug-induced toxicity. Additionally, we highlight experimental outcomes of alcohol/drug-induced toxicity and potential treatment strategies. Finally, we cover the role and implications of extracellular vesicles (EVs) containing CYP2E1 in hepatic and extrahepatic cells and provide perspectives on the clinical relevance of EVs containing CYP2E1 in intracellular and intercellular communications leading to drug-drug and alcohol-drug interactions. Furthermore, we provide our perspectives on CYP2E1 as a druggable target using nutraceuticals and the use of EVs for targeted drug delivery in extrahepatic and hepatic cells, especially to treat cellular toxicity.
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2
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Binmahfouz LS, Bagher AM. Genetic polymorphism of the drug-metabolizing enzyme Cytochrome P4502E1 (CYP2E1) in a healthy Saudi population. Saudi Pharm J 2021; 29:1355-1360. [PMID: 34819796 PMCID: PMC8596149 DOI: 10.1016/j.jsps.2021.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 09/24/2021] [Indexed: 11/04/2022] Open
Abstract
Objectives Cytochrome P450 2E1 (CYP2E1) is one of the major enzymes involved in the metabolism and detoxification of various drugs and xenobiotics. Polymorphisms in the CYP2E1 gene exhibit high inter-individual variations associated with alterations in CYP2E1 gene expression and enzyme function. This study aimed to determine the genotype distributions and allele frequencies of CYP2E1*1B, *5B, and *6 polymorphisms among Saudis in western Saudi Arabia. Methods In total, 140 healthy Saudis attending King Abdulaziz University Hospital between February and April 2021 were included in the study. CYP2E1 gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Results The genotype frequencies of CYP2E1*1B A2A2, A2A1, and A1A1 were 54.29%, 40%, and 8%, respectively. The frequencies of CYP2E1*5B c1c1 and c1c2 genotypes were approximately 99.93% and 0.07%, respectively. The frequencies of the CYP2E1*6 DD, DC, and CC genotypes were 91.43%, 7.85%, and 0.72%, respectively. The genotype distributions for these polymorphisms were consistent with the expected distribution based on Hardy-Weinberg equilibrium. The allele frequencies were 74.29% A2 and 25.71% A1 for CYP2E1*1B, 99.64% c1 and 0.36% c2 for CYP2E1*5B, and 95.36% D and 4.65% C for CYP2E1*6. Conclusion The genotype distribution of CYP2E1*1B polymorphism was higher in the western Saudi population, whereas the CYP2E1*5B and *6 polymorphisms were lower than the global average. Knowledge of the prevalence of CYP2E1 polymorphisms among our population will provide a better understanding of whether individual patients might benefit from their medication or whether they might develop adverse effects.
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Affiliation(s)
- Lenah S Binmahfouz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King AbdulAziz University, Jeddah, Saudi Arabia
| | - Amina M Bagher
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King AbdulAziz University, Jeddah, Saudi Arabia
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3
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Matsumoto S, Uehara S, Kamimura H, Ikeda H, Maeda S, Hattori M, Nishiwaki M, Kato K, Yamazaki H. Human total clearance values and volumes of distribution of typical human cytochrome P450 2C9/19 substrates predicted by single-species allometric scaling using pharmacokinetic data sets from common marmosets genotyped for P450 2C19. Xenobiotica 2021; 51:479-493. [PMID: 33455494 DOI: 10.1080/00498254.2020.1871113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Common marmosets (Callithrix jacchus) are small non-human primates that genetically lack cytochrome P450 2C9 (CYP2C9). Polymorphic marmoset CYP2C19 compensates by mediating oxidations of typical human CYP2C9/19 substrates.Twenty-four probe substrates were intravenously administered in combinations to marmosets assigned to extensive or poor metaboliser (PM) groups by CYP2C19 genotyping. Eliminations from plasma of cilomilast, phenytoin, repaglinide, tolbutamide, and S-warfarin in the CYP2C19 PM group were significantly slow; these drugs are known substrates of human CYP2C8/9/19.Human total clearance values and volumes of distribution of the 24 test compounds were extrapolated using single-species allometric scaling with experimental data from marmosets and found to be mostly comparable with the reported values.Human total clearance values and volumes of distribution of 15 of the 24 test compounds similarly extrapolated using reported data sets from cynomolgus or rhesus monkeys were comparable to the present predicted results, especially to those based on data from PM marmosets.These results suggest that single-species allometric scaling using marmosets, being small, has advantages over multiple-species-based allometry and could be applicable for pharmacokinetic predictions at the discovery stage of drug development.
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Affiliation(s)
- Shogo Matsumoto
- Pharmaceutical Research Labs., Meiji Seika Pharma Co., Ltd., Yokohama, Japan
| | - Shotaro Uehara
- Central Institute for Experimental Animals, Kawasaki, Japan.,Pharmaceutical University, Machida, Tokyo, Japan
| | - Hidetaka Kamimura
- Central Institute for Experimental Animals, Kawasaki, Japan.,Business Promotion Dept., CLEA Japan, Inc., Tokyo, Japan
| | - Hiroshi Ikeda
- Tokyo Animal & Diet Dept., CLEA Japan, Inc., Tokyo, Japan
| | - Satoshi Maeda
- Yaotsu Breeding Center, CLEA Japan, Inc., Gifu, Japan
| | | | - Megumi Nishiwaki
- Fuji Technical Service Center, CLEA Japan, Inc.., Shizuoka, Japan
| | - Kazuhiko Kato
- Pharmaceutical Research Labs., Meiji Seika Pharma Co., Ltd., Yokohama, Japan
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4
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The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study. J Med Toxicol 2020; 17:160-167. [PMID: 33051802 DOI: 10.1007/s13181-020-00815-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen. METHODS We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program. RESULTS We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53). CONCLUSIONS While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.
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Abstract
Acetaminophen (APAP) is perhaps the most commonly used drug both inside and outside the hospital due to its relative safety and over-the-counter availability. Despite its safety, it can cause drug-related side effects, especially acute liver injury that can be unpredictable. Additionally, due to its variable, delayed and nonspecific symptomatology, it can pose a significant diagnostic challenge. Due to potential reversibility with an antidote and adverse outcome related to liver failure, timely recognition and treatment is key in suspected toxicity. Here we present a case of a young female who presented for the evaluation of seizure and found to have APAP-related liver failure with only 2 g of APAP taken over two days duration.
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Affiliation(s)
- Ahmad Raza
- Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA
| | - Vincent Chan
- Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA
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Borro M, Guglielmetti M, Simmaco M, Martelletti P, Gentile G. The future of pharmacogenetics in the treatment of migraine. Pharmacogenomics 2019; 20:1159-1173. [PMID: 31637960 DOI: 10.2217/pgs-2019-0069] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Migraine is considered one of the most disabling neurological disorder with a high socioeconomic burden. Pharmacological management includes many classes of drugs which in the most cases, are administrated in polytherapy. The therapeutic scheme of migraineurs is often affected by comorbidities which need concomitant medications, thus increasing the risk of side effects related to drug-drug interactions. Pharmacogenetics is a promising tool to achieve a personalized cure based on individual genetic profile while the availability of free online knowledge bases allows to check the potential DDIs of selected medications. Combining, these approaches may offer to clinicians a useful tool to improve the appropriateness of migraine polytherapy choice, aiming to increase the efficacy and reduce the toxicity of pharmacological treatments.
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Affiliation(s)
- Marina Borro
- Department of Neurosciences, Mental Health & Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.,Laboratory of Clinical Chemistry, Sant'Andrea Hospital, Rome, Italy
| | - Martina Guglielmetti
- Department of Clinical & Molecular Medicine, Sapienza University of Rome, Rome, Italy.,Regional Referral Headache Centre, Sant'Andrea Hospital, Rome, Italy.,Department of Clinical Pathology, University of Sassari, Sassari, Italy
| | - Maurizio Simmaco
- Department of Neurosciences, Mental Health & Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.,Laboratory of Clinical Chemistry, Sant'Andrea Hospital, Rome, Italy
| | - Paolo Martelletti
- Department of Clinical & Molecular Medicine, Sapienza University of Rome, Rome, Italy.,Regional Referral Headache Centre, Sant'Andrea Hospital, Rome, Italy
| | - Giovanna Gentile
- Department of Neurosciences, Mental Health & Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.,Laboratory of Clinical Chemistry, Sant'Andrea Hospital, Rome, Italy
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Awad H, Ahmed A, Urman RD, Stoicea N, Bergese SD. Potential role of pharmacogenomics testing in the setting of enhanced recovery pathways after surgery. Pharmgenomics Pers Med 2019; 12:145-154. [PMID: 31440074 PMCID: PMC6666379 DOI: 10.2147/pgpm.s198224] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 07/10/2019] [Indexed: 11/23/2022] Open
Abstract
In 2001, a group of European academic surgeons created the Enhanced Recovery After Surgery (ERAS) study group and established the first official ERAS protocol. One of the most significant challenges during ERAS implementation is variability of drugs used throughout the perioperative period. Pharmacogenomic testing (blood or saliva) results (obtained within approximately 48 hrs) provide guidelines on how to prescribe the optimal drug with the optimal dosage to each patient based on an individual's unique genetic profile. Pharmacogenomic testing of various methods of multimodal analgesia is an essential element of ERAS protocols spanning the entire perioperative period to ultimately optimize postoperative pain control. The key goal for anesthetic management in ERAS protocols is to facilitate rapid emergence by using the shortest acting agents available, thus accelerating recovery and reducing length of stay, hospital expenses, and postoperative complications. Postoperative nausea and vomiting (PONV) is an additional challenge that should be overcome to ensure an enhanced recovery and shorter length of stay with the use of antiemetics. Postoperative ileus (POI) can result in longer hospital stay with increasing susceptibility to associated morbidities along with an increase in associated hospitalization costs. Genetics-guided pharmacotherapy and its impact on clinical outcomes should be thoroughly studied for better understanding and managing drug administration in the settings of ERAS.
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Affiliation(s)
- Hamdy Awad
- Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ahmed Ahmed
- Department of Anesthesiology, The University of Texas, Houston, TX, USA
| | - Richard D Urman
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Nicoleta Stoicea
- Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sergio D Bergese
- Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Chen J, Jiang S, Wang J, Renukuntla J, Sirimulla S, Chen J. A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism. Drug Metab Rev 2019; 51:178-195. [PMID: 31203697 DOI: 10.1080/03602532.2019.1632889] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cytochrome P450 2E1 (CYP2E1) plays a vital role in drug-induced hepatotoxicity and cancers (e.g. lung and bladder cancer), since it is responsible for metabolizing a number of medications and environmental toxins to reactive intermediate metabolites. CYP2E1 was recently found to be the highest expressed CYP enzyme in human livers using a proteomics approach, and CYP2E1-related toxicity is strongly associated with its protein level that shows significant inter-individual variability related to ethnicity, age, and sex. Furthermore, the expression of CYP2E1 demonstrates regulation by extensive genetic polymorphism, endogenous hormones, cytokines, xenobiotics, and varying pathological states. Over the past decade, the knowledge of pharmacology, toxicology, and biology about CYP2E1 has grown remarkably, but the research progress has yet to be summarized. This study presents a timely systematic review on CYP2E1's xenobiotic metabolism, genetic polymorphism, and inhibitors, with the focus on their clinical relevance for the efficacy and toxicity of various CYP2E1 substrates. Moreover, several knowledge gaps have been identified towards fully understanding the potential interactions among different CYP2E1 substrates in clinical settings. Through in-depth analyses of these knowns and unknowns, we expect this review will aid in future drug development and improve management of CYP2E1 related clinical toxicity.
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Affiliation(s)
- Jingxuan Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University , Guangzhou , China
| | - Sibo Jiang
- Department of Pharmaceutics, University of Florida , Orlando , FL , USA
| | - Jin Wang
- AbbVie Inc , North Chicago , IL , USA
| | - Jwala Renukuntla
- School of Pharmacy, The University of Texas at El Paso , El Paso , TX , USA
| | - Suman Sirimulla
- School of Pharmacy, The University of Texas at El Paso , El Paso , TX , USA
| | - Jianjun Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University , Guangzhou , China
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9
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Park SI, Park JY, Lee JH, Park MS, Lee KT, Yim SV, Yoon YR, Kim BH. Pharmacokinetic Analysis and Biomarker-Assisted Safety Assessment of Acetaminophen in Combination With Ojeok-san Compared With Acetaminophen Alone. J Clin Pharmacol 2019; 59:1485-1494. [PMID: 31090078 DOI: 10.1002/jcph.1439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/15/2019] [Indexed: 02/05/2023]
Abstract
Acetaminophen and Ojeok-san are both frequently used analgesics. In this study, we evaluated acetaminophen pharmacokinetics (PK) and changes in microRNA-122 (miR-122) levels after multiple dosing of acetaminophen with or without Ojeok-san. An open-label, 1-sequence, 2-period, 2-treatment crossover study was conducted in 18 subjects. In period 1, 500 mg of acetaminophen was administered 3 times on day 1 and once on day 2. In period 2, after the administration of 14.47 g of Ojeok-san twice on day 2 and 3 times daily on days 3 to 7, Ojeok-san and acetaminophen were coadministered 3 times each on day 8 and once each on day 9. The geometric mean ratios (90% confidence intervals) of acetaminophen with Ojeok-san to acetaminophen alone were 0.98 (0.87 to 1.10) and 1.02 (0.98 to 1.05) for the maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve during the dosing interval (AUC0-τ ), respectively, of acetaminophen at steady state. The alanine aminotransferase (ALT) levels were within the reference range in all the participants throughout the study period, although the mean fold changes in both serum miR-122 and ALT levels from baseline tended to increase on days 2 to 5. In conclusion, the PK properties of acetaminophen were not significantly affected by Ojeok-san coadministration. For osteoarthritis patients taking acetaminophen with or without Ojeok-san, monitoring potential liver toxicity using miR-122 as a biomarker may be useful.
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Affiliation(s)
- Sang-In Park
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Seoul, Republic of Korea.,East-West Medical Research Institute, Kyung Hee University, Seoul, Republic of Korea
| | - Ji-Young Park
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ji Hyun Lee
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.,Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.,Department of Biomedical Science and Technology, Kyung Hee University, Seoul, Republic of Korea
| | - Mun Su Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Kyung-Tae Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.,Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Sung-Vin Yim
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Seoul, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Young-Ran Yoon
- School of Medicine, Kyungpook National University and Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Bo-Hyung Kim
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Seoul, Republic of Korea.,East-West Medical Research Institute, Kyung Hee University, Seoul, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.,Department of Biomedical Science and Technology, Kyung Hee University, Seoul, Republic of Korea
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10
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Heruth DP, Shortt K, Zhang N, Li DY, Zhang LQ, Qing Ye S. Genetic Association of Single Nucleotide Polymorphisms with Acetaminophen-Induced Hepatotoxicity. J Pharmacol Exp Ther 2018; 367:95-100. [PMID: 30076262 DOI: 10.1124/jpet.118.248583] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 08/01/2018] [Indexed: 12/15/2022] Open
Abstract
Acetaminophen is commonly used to reduce pain and fever. Unfortunately, overdose of acetaminophen is a leading cause of acute liver injury and failure in many developed countries. The majority of acetaminophen is safely metabolized in the liver and excreted in the urine; however, a small percentage is converted to the highly reactive N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is inactivated by glutathione S-transferases, but at toxic levels, excess NAPQI forms reactive protein adducts that lead to hepatotoxicity. Individual variability in the response to both therapeutic and toxic levels of acetaminophen suggests a genetic component is involved in acetaminophen metabolism. In this review, we evaluate the genetic association studies that have identified 147 single nucleotide polymorphisms linked to acetaminophen-induced hepatotoxicity. The identification of novel genetic markers for acetaminophen-induced hepatotoxicity provides a rich resource for further evaluation and may lead to improved prognosis, prevention, and treatment.
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Affiliation(s)
- Daniel P Heruth
- Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy (D.P.H., K.S., N.Z., L.Q.Z., S.Q.Y.), Division of Gastroenterology, Department of Pediatrics, Children's Mercy (N.Z., D.-Y.L.), and Department of Biomedical and Health Informatics (K.S., S.Q.Y.), University of Missouri Kansas City School of Medicine, Kansas City, Missouri; Division of Cell Biology and Biophysics, University of Missouri Kansas City School of Biological Sciences, Kansas City, Missouri (K.S.); and Department of Pediatrics, Tangdu Hospital, The Fourth Military Medical University, Xian, China (N.Z.)
| | - Katherine Shortt
- Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy (D.P.H., K.S., N.Z., L.Q.Z., S.Q.Y.), Division of Gastroenterology, Department of Pediatrics, Children's Mercy (N.Z., D.-Y.L.), and Department of Biomedical and Health Informatics (K.S., S.Q.Y.), University of Missouri Kansas City School of Medicine, Kansas City, Missouri; Division of Cell Biology and Biophysics, University of Missouri Kansas City School of Biological Sciences, Kansas City, Missouri (K.S.); and Department of Pediatrics, Tangdu Hospital, The Fourth Military Medical University, Xian, China (N.Z.)
| | - Nini Zhang
- Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy (D.P.H., K.S., N.Z., L.Q.Z., S.Q.Y.), Division of Gastroenterology, Department of Pediatrics, Children's Mercy (N.Z., D.-Y.L.), and Department of Biomedical and Health Informatics (K.S., S.Q.Y.), University of Missouri Kansas City School of Medicine, Kansas City, Missouri; Division of Cell Biology and Biophysics, University of Missouri Kansas City School of Biological Sciences, Kansas City, Missouri (K.S.); and Department of Pediatrics, Tangdu Hospital, The Fourth Military Medical University, Xian, China (N.Z.)
| | - Ding-You Li
- Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy (D.P.H., K.S., N.Z., L.Q.Z., S.Q.Y.), Division of Gastroenterology, Department of Pediatrics, Children's Mercy (N.Z., D.-Y.L.), and Department of Biomedical and Health Informatics (K.S., S.Q.Y.), University of Missouri Kansas City School of Medicine, Kansas City, Missouri; Division of Cell Biology and Biophysics, University of Missouri Kansas City School of Biological Sciences, Kansas City, Missouri (K.S.); and Department of Pediatrics, Tangdu Hospital, The Fourth Military Medical University, Xian, China (N.Z.)
| | - Li Q Zhang
- Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy (D.P.H., K.S., N.Z., L.Q.Z., S.Q.Y.), Division of Gastroenterology, Department of Pediatrics, Children's Mercy (N.Z., D.-Y.L.), and Department of Biomedical and Health Informatics (K.S., S.Q.Y.), University of Missouri Kansas City School of Medicine, Kansas City, Missouri; Division of Cell Biology and Biophysics, University of Missouri Kansas City School of Biological Sciences, Kansas City, Missouri (K.S.); and Department of Pediatrics, Tangdu Hospital, The Fourth Military Medical University, Xian, China (N.Z.)
| | - Shui Qing Ye
- Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy (D.P.H., K.S., N.Z., L.Q.Z., S.Q.Y.), Division of Gastroenterology, Department of Pediatrics, Children's Mercy (N.Z., D.-Y.L.), and Department of Biomedical and Health Informatics (K.S., S.Q.Y.), University of Missouri Kansas City School of Medicine, Kansas City, Missouri; Division of Cell Biology and Biophysics, University of Missouri Kansas City School of Biological Sciences, Kansas City, Missouri (K.S.); and Department of Pediatrics, Tangdu Hospital, The Fourth Military Medical University, Xian, China (N.Z.)
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11
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Henderson LM, Claw KG, Woodahl EL, Robinson RF, Boyer BB, Burke W, Thummel KE. P450 Pharmacogenetics in Indigenous North American Populations. J Pers Med 2018; 8:jpm8010009. [PMID: 29389890 PMCID: PMC5872083 DOI: 10.3390/jpm8010009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 01/19/2018] [Accepted: 01/22/2018] [Indexed: 12/14/2022] Open
Abstract
Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy.
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Affiliation(s)
- Lindsay M Henderson
- Departments of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
| | - Katrina G Claw
- Departments of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
| | - Erica L Woodahl
- Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
| | - Renee F Robinson
- Southcentral Foundation, Anchorage, AK 99508, USA.
- United States Public Health Service, Department of Human Services, Washington, DC 20201, USA.
| | - Bert B Boyer
- Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, AK 99775, USA.
| | - Wylie Burke
- Bioethics & Humanities, University of Washington, Seattle, WA 98195, USA.
| | - Kenneth E Thummel
- Departments of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
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12
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Le paracétamol à dose thérapeutique : quelles populations à risque d’hépatotoxicité ? TOXICOLOGIE ANALYTIQUE ET CLINIQUE 2018. [DOI: 10.1016/j.toxac.2017.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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13
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Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J Clin Transl Hepatol 2016; 4:131-42. [PMID: 27350943 PMCID: PMC4913076 DOI: 10.14218/jcth.2015.00052] [Citation(s) in RCA: 244] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 04/07/2016] [Accepted: 05/18/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways.
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Affiliation(s)
- Eric Yoon
- Rutgers New Jersey Medical School, University Hospital, Newark, New Jersey, USA
| | - Arooj Babar
- Rutgers New Jersey Medical School, University Hospital, Newark, New Jersey, USA
| | - Moaz Choudhary
- Rutgers New Jersey Medical School, University Hospital, Newark, New Jersey, USA
| | - Matthew Kutner
- Rutgers New Jersey Medical School, University Hospital, Newark, New Jersey, USA
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PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics 2016; 25:416-26. [PMID: 26049587 DOI: 10.1097/fpc.0000000000000150] [Citation(s) in RCA: 201] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Mishima-Iwai M, Takahashi K, Yokode M, Kimura Y, Sawai Y, Ueda Y, Chiba T. Late-onset acetaminophen-induced allergic hepatitis with progression to chronicity. Hepatol Res 2015; 45:814-7. [PMID: 25088083 DOI: 10.1111/hepr.12399] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 07/14/2014] [Accepted: 07/28/2014] [Indexed: 12/28/2022]
Abstract
Acetaminophen (paracetamol), a widely used antipyretic/analgesic, is a well-known agent causing acute hepatic injury. Whereas most cases are caused by its intrinsic hepatotoxicity, idiosyncratic hepatitis by the allergic mechanism is extremely rare. We herein report a case of late-onset acetaminophen-induced allergic hepatitis with progression to chronicity. This unique case extends the spectrum of acetaminophen-induced liver injury. Clinicians should be aware of this unusual clinical manifestation. The mechanism underlying the immunological reaction to acetaminophen remains to be elucidated.
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Affiliation(s)
- Masako Mishima-Iwai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Takahashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masataka Yokode
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshito Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yugo Sawai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Krasniak AE, Knipp GT, Svensson CK, Liu W. Pharmacogenomics of acetaminophen in pediatric populations: a moving target. Front Genet 2014; 5:314. [PMID: 25352860 PMCID: PMC4196544 DOI: 10.3389/fgene.2014.00314] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 08/21/2014] [Indexed: 11/22/2022] Open
Abstract
Acetaminophen (APAP) is widely used as an over-the-counter fever reducer and pain reliever. However, the current therapeutic use of APAP is not optimal. The inter-patient variability in both efficacy and toxicity limits the use of this drug. This is particularly an issue in pediatric populations, where tools for predicting drug efficacy and developmental toxicity are not well established. Variability in toxicity between age groups may be accounted for by differences in metabolism, transport, and the genetics behind those differences. While pharmacogenomics has been revolutionizing the paradigm of pharmacotherapy for many drugs, its application in pediatric populations faces significant challenges given the dynamic ontogenic changes in cellular and systems physiology. In this review we focused on the ontogenesis of the regulatory pathways involved in the disposition of APAP and on the variability between pediatric, adolescent, and adult patients. We also summarize important polymorphisms of the pharmacogenes associated with APAP metabolism. Pharmacogenetic studies in pediatric APAP treatment are also reviewed. We conclude that while a consensus in pharmacogenetic management of APAP in pediatric populations has not been achieved, a systems biology based strategy for comprehensively understanding the ontogenic regulatory pathway as well as the interaction between age and genetic variations are particularly necessary in order to address this question.
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Affiliation(s)
- Anne E. Krasniak
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA
| | - Gregory T. Knipp
- Industrial and Physical Pharmacy, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA
| | - Craig K. Svensson
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA
| | - Wanqing Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA
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17
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Gentile G, Chiossi L, Lionetto L, Martelletti P, Borro M. Pharmacogenetic insights into migraine treatment in children. Pharmacogenomics 2014; 15:1539-50. [DOI: 10.2217/pgs.14.104] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pediatric migraine is a disabling condition that can affect the everyday activities and emotional states of children. Due to the multifactorial character of the pathology and the variety of the disease's phenotypes, establishment of an effective treatment is often challenging. Pharmacological treatment is often administered off-label and includes very different drugs, from analgesics to antidepressants. Since interindividual variability in therapy response commonly causes inefficacy and an exacerbation of symptoms, pharmacogenetics may help to decrease the prescription rate of useless or unsafe drugs. If there are many drugs used in migraine, then there are even more candidate or established pharmacogenetic markers that are implicated in clinical profiles. This article presents the current situation regarding the pharmacogenetics of drugs used in pediatric migraine.
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Affiliation(s)
| | | | - Luana Lionetto
- Advanced Molecular Diagnostic Unit (DiMA), Sant’Andrea Hospital, Rome, Italy
| | - Paolo Martelletti
- Regional Referral Headache Center, Sant’Andrea Hospital, Rome, Italy
- Department of Clinical & Molecular Medicine (DCMM), Sapienza University of Rome, Rome, Italy
| | - Marina Borro
- NESMOS Department, Sapienza University of Rome, Rome, Italy
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Chomchai S, Chomchai C. Predicting acute acetaminophen hepatotoxicity with acetaminophen-aminotransferase multiplication product and the Psi parameter. Clin Toxicol (Phila) 2014; 52:506-11. [DOI: 10.3109/15563650.2014.917180] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Marotta SE, Belchikov Y, Siegel MD. Hypothermia and protection from acetaminophen-induced liver injury. Ther Hypothermia Temp Manag 2014; 1:57-60. [PMID: 24716888 DOI: 10.1089/ther.2010.0005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Acetaminophen-induced liver failure is the most common cause of acute liver failure in the United States. The exact mechanism of acute liver failure secondary to acetaminophen toxicity is unknown, although a presumed mechanism of hepatocellular necrosis involving the accumulation of a toxic metabolite (N-acetyl-p-benzoquinoneimine) has been postulated. A 62-year-old woman with a history of a suicide attempt was brought to the emergency department at ∼12 hours post acetaminophen overdose. The patient presented with an acetaminophen level of 284 mcg/mL and with profound hypothermia (31°C). Liver function tests and coagulation studies were normal. Within 24 hours of presentation, the patient was normothermic, had received seven oral doses of N-acetylcysteine, and had an acetaminophen level of <5 mcg/mL. The patient was discharged from the intensive care unit at 96 hours post admission in stable condition with no evidence of hepatic injury. No further treatment with N-acetylcysteine was required. Despite a toxic acetaminophen level, this patient did not suffer any hepatic injury. Hypothermia may have attenuated the production of N-acetyl-p-benzoquinoneimine by depressing the cytochrome P450 system, allowing accumulation of the parent drug rather than toxic metabolites. This case report suggests that hypothermia may have protected the liver of a patient presenting with acetaminophen toxicity and supports further investigation into the potential therapeutic role of induced hypothermia during acetaminophen toxicity.
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Affiliation(s)
- Sandra E Marotta
- 1 Critical Care Pharmacist, Yale-New Haven Hospital , New Haven, Connecticut
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Marzuillo P, Guarino S, Barbi E. Paracetamol: a focus for the general pediatrician. Eur J Pediatr 2014; 173:415-25. [PMID: 24374658 DOI: 10.1007/s00431-013-2239-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 12/05/2013] [Indexed: 02/02/2023]
Abstract
UNLABELLED Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever in children. This drug has multiple mechanisms of action, but its pharmacodynamic is still not well known. The central nervous system is the main site of action and it mirrors the paracetamol effect compartment. The recommended dosages and routes of administration should be different whether paracetamol is used for the treatment of pain or fever. For example, the rectal route, while being efficacious for the treatment of fever, should be avoided in pain management. Paracetamol is a safe drug, but some clinical conditions and concomitant drugs, which are frequent in clinical practice, may increase the risk of paracetamol toxicity. Therefore, it is important to optimize its administration to avoid overdoses and maximize its effect. The principal mediator of the paracetamol toxicity is the N-acetyl-p-benzo-quinone imine (NAPQI), a toxic product of the paracetamol metabolism, which could bind cysteine groups on proteins forming paracetamol-protein adduct in the liver. CONCLUSION Although frequently prescribed, the concept of "effect compartment concentration" and the possible co-factors that could cause toxicity at recommended doses are not familiar to all pediatricians and general practitioners. We reviewed the literature concerning paracetamol mechanisms of action, we highlighted some relevant pharmacodynamic concepts for clinical practice, and we summarized the possible risk factors for toxicity at therapeutic dosages.
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Affiliation(s)
- Pierluigi Marzuillo
- Department of Women and Children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, Via L. De Crecchio 2, 80138, Naples, Italy,
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21
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Navid A, Ng DM, Stewart BJ, Wong SE, Lightstone FC. Quantitative In Silico analysis of transient metabolism of acetaminophen and associated causes of hepatotoxicity in humans. In Silico Pharmacol 2013. [PMCID: PMC4750864 DOI: 10.1186/2193-9616-1-14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Abstract
Acetaminophen (APAP) is the leading worldwide cause of drug overdose and acute liver failure (ALF). Single overdose ingestion and therapeutic misadventure may cause hepatotoxicity. Several factors, such as concomitant alcohol use or abuse, concurrent medications, genetic factors, and nutritional status, can influence the susceptibility and severity of APAP hepatotoxicity. Early manifestations of APAP hepatotoxicity are nonspecific, but require prompt recognition by physicians. Patients with repeated overdose tend to present late, and in such hepatotoxicity may have already evolved. N-acetylcysteine is a very effective antidote when giving within 8 hours, and is also recommended after a presentation of hepatotoxicity and ALF. The prognosis of patients with APAP-induced ALF is better than other causes of ALF. Liver transplantation should be offered to those who are unlikely to survive.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
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Celorrio D, Bujanda L, Caso C, Landabaso M, Oria JC, Ogando J, de Pancorbo MM. A comparison of Val81Met and other polymorphisms of alcohol metabolising genes in patients and controls in Northern Spain. Alcohol 2012; 46:427-31. [PMID: 22560290 DOI: 10.1016/j.alcohol.2012.03.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 02/13/2012] [Accepted: 03/22/2012] [Indexed: 01/20/2023]
Abstract
The aim of this paper is to study polymorphism in the TH, ADH1B, ADH1C, ALDH2 and CYP2E1 genes so as to ascertain whether it is associated with excessive consumption of alcohol. The SNPs rs6356 of TH, rs1229984, rs2066702 of ADH1B; rs698, rs1693482 of ADH1C; rs671 of ALDH2; rs72559710, rs55897648, rs6413419, rs3813867, rs2031920, rs6413432 of CYP2E1 were studied in a sample of 172 high-level patients and 150 fully non-drinkers controls. Genotyping was performed using Rt-PCR with Taqman probes. SNPs located at ALDH2 and CYP2E1 showed no heterozygosity. Frequency distribution showed significant differences between the two groups studied for loci TH and ADH1B. The genotype Val/Val of TH locus increased in risk 1.988 times (95% CI: 1.006-3.930) that the subjects carrying the genotype Met/Met; and the genotype ADH1B*1/*1 of ADH1B locus increased in risk 3.811 times (CI: 1.660-8.749) that the subjects carrying the genotype ADH1B*1/*2. Alleles Val and ADH1B*1 may therefore increase the risk of the onset and development of this illness.
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Chomchai S, Chomchai C, Anusornsuwan T. Acetaminophen psi parameter: A useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose. Clin Toxicol (Phila) 2011; 49:664-7. [DOI: 10.3109/15563650.2011.597031] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Savino F, Lupica MM, Tarasco V, Locatelli E, Garazzino S, Tovo PA. Fulminant hepatitis after 10 days of acetaminophen treatment at recommended dosage in an infant. Pediatrics 2011; 127:e494-7. [PMID: 21242227 DOI: 10.1542/peds.2010-1965] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Acetaminophen is considered a safe drug for children, although hepatotoxicity may develop after overdosing. Reports of liver failure after repeated therapeutic doses of the drug have been rare. Here we describe the case of an infant who developed acute liver failure after administration of acetaminophen for 10 days at a total dose of 720 mg/day (72 mg/kg per day). The patient had high levels of aspartate aminotransferase (11 735 U/L) and alanine aminotransferase (6611 U/L) accompanied by encephalopathy and an increased ammonium level (266 μg/dL). Intravenous N-acetylcysteine therapy resulted in rapid improvement of the child's clinical condition and laboratory test results. Health care providers should be aware that multiple doses of acetaminophen in infants may lead to acute hepatic failure. N-acetylcysteine therapy should be initiated in cases of drug-induced acute liver failure.
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Affiliation(s)
- Francesco Savino
- Department of Paediatrics, Ospedale Infantile Regina Margherita, Turin, Italy.
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Acetaminophen dose does not predict outcome in acetaminophen-induced acute liver failure. J Investig Med 2010; 58:707-10. [PMID: 20305573 DOI: 10.231/jim.0b013e3181db8764] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Acetaminophen is a dose-dependent toxin. Prognosis in severe acute liver injury is related presumably in part to the dose ingested. We sought to assess the value of acetaminophen dosing information in patients with acute liver failure (ALF) due to acetaminophen toxicity to determine the role of dose as a prognostic indicator. METHODS Prospective data from 113 patients with ALF having single-time-point ingestions of acetaminophen were analyzed. Multivariate and chi tests were used to determine the relationship of dose to clinical outcome. We also used the Mann-Whitney U test to compare prognosis and survival in ALF with acetaminophen dose ingested. RESULTS Multivariate and chi analyses failed to show any relationship between acetaminophen dose and spontaneous survival. A separate analysis showed no correlation between acetaminophen dose and clinical prognostic indicators. CONCLUSIONS Dose of acetaminophen ingested did not seem to play a role in prognosis. The most important prognostic factor was coma grade on admission to study. Acetaminophen dosing information is not always obtainable. When it is, it adds little to the clinical assessment. Severity of encephalopathy is a more reliable indicator of prognosis in these critically ill patients.
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Gordillo-Bastidas E, Panduro A, Gordillo-Bastidas D, Zepeda-Carrillo EA, García-Bañuelos JJ, Muñoz-Valle JF, Bastidas-Ramírez BE. Polymorphisms of alcohol metabolizing enzymes in indigenous Mexican population: unusual high frequency of CYP2E1*c2 allele. Alcohol Clin Exp Res 2009; 34:142-9. [PMID: 19860798 DOI: 10.1111/j.1530-0277.2009.01075.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Alcohol abuse represents the major identified etiological factor of cirrhosis in México. ADH1B, ALDH2, and CYP2E1 have been considered candidate genes in alcohol-related diseases. Controversial results probably due to ethnic differences, among other factors, have been reported. Mexican Mestizos (MES) derive from the combination of indigenous, Spaniard, and African genes. Huichols (HUI) constitute an indigenous group from western Mexico with no racial admixture. We determined ADH1B*2, ALDH2*2, and CYP2E1*c2 allele frequencies in healthy HUI and MES from western Mexico. Lipid and hepatic profile were also carried out. METHODS One hundred and one HUI and 331 MES subjects were studied. Genotype and allele frequency were assessed through polymerase chain reaction-restriction fragment length polymorphism after DNA isolation from peripheral leukocytes. Commercial kits for lipid and hepatic determinations were used. RESULTS Polymorphic allele distribution in HUI was: 0%ADH1B*2, 0.5%ALDH2*2, 51.5%CYP2E1*c2; in MES: 3.4%ADH1B*2, 0%ALDH2*2, 16.1%CYP2E1*c2. Frequency of ADH1B*2 was statistically (p < 0.001) lower in HUI than MES. CYP2E1*c2 polymorphic allele was significantly higher (p < 0.0001) in HUI than MES. Hepatic profile was normal in both groups. HUI showed a better lipid profile than MES independently of genotype. CONCLUSIONS Huichols exhibited the highest CYP2E1*c2 allele frequency of the world documented up to this date; meanwhile, ADH1B*2 and ALDH2*2 were practically absent. This feature could be useful in the understanding of Mexican population gene composition, alcohol metabolism, and alcoholic liver disease development. However, further association studies are necessary. The heterogeneity of Mexican population was evidenced by the significantly different distribution of CYP2E1*c2 allele observed among different regions of the country. Lipid and hepatic values were not associated to genotype. This report constitutes the first study dealing with gene polymorphisms of alcohol metabolizing enzymes conducted in HUI.
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Affiliation(s)
- Elizabeth Gordillo-Bastidas
- Instituto de Enfermedades Crónico-Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, México.
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Toxicogenomics and clinical toxicology: An example of the connection between basic and applied sciences. Toxicol Lett 2009; 186:2-8. [DOI: 10.1016/j.toxlet.2008.10.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2008] [Revised: 10/27/2008] [Accepted: 10/28/2008] [Indexed: 11/22/2022]
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Neafsey P, Ginsberg G, Hattis D, Johns DO, Guyton KZ, Sonawane B. Genetic polymorphism in CYP2E1: Population distribution of CYP2E1 activity. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2009; 12:362-388. [PMID: 20183527 DOI: 10.1080/10937400903158359] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cytochrome P-450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of a variety of toxicants including nitrosamines, benzene, vinyl chloride, and halogenated solvents such as trichloroethylene. CYP2E1 is also one of the enzymes that metabolizes ethanol to acetaldehyde, and is induced by recent ethanol ingestion. There is evidence that interindividual variability in the expression and functional activity of this cytochrome (CYP) may be considerable. Genetic polymorphisms in CYP2E1 were identified and linked to altered susceptibility to hepatic cirrhosis induced by ethanol and esophageal and other cancers in some epidemiological studies. Therefore, it is important to evaluate how such polymorphisms affect CYP2E1 function and whether it is possible to construct a population distribution of CYP2E1 activity based upon the known effects of these polymorphisms and their frequency in the population. This analysis is part of the genetic polymorphism database project described in the lead article in this series and followed the approach described in that article (Ginsberg et al., 2009, this issue). Review of the literature found that there are a variety of CYP2E1 variant alleles but the functional significance of these variants is still unclear. Some, but not all, studies suggest that several upstream 5' flanking mutations affect gene expression and response to inducers such as ethanol or obesity. None of the coding-region variants consistently affects enzyme function. Part of the reason for conflicting evidence regarding genotype effect on phenotype may be due to the wide variety of exposures such as ethanol or dietary factors and physiological factors including body weight or diabetes that modulate CYP2E1 expression. In conclusion, evidence is too limited to support the development of a population distribution of CYP2E1 enzyme activity based upon genotypes. Health risk assessments may best rely upon data reporting interindividual variability in CYP2E1 function for input into physiologically based pharmacokinetic (PBPK) models involving CYP2E1 substrates.
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Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis. Hepatology 2008; 48:1336-41. [PMID: 18821593 DOI: 10.1002/hep.22536] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Acute liver injury (ALI) following acetaminophen overdose (AO) occurs in less than 10% of cases, but that risk is increased among alcoholics and those with chronic alcoholic liver disease. We sought to assess whether coexistent hepatitis C virus (HCV) infection potentiated the hepatotoxic effects of acetaminophen. We queried the Nationwide Inpatient Sample (1998-2005), a 20% sample of U.S. hospitals, to identify admissions for AO using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Outcomes were development of ALI (ICD-9-CM: 570.0, 572.2, 573.3), in-hospital mortality, severe liver failure, and resource utilization. There were 42,781 admissions for AO in the sample, yielding a national estimate of 210,436 AO hospitalizations. HCV prevalence increased from 0.5% to 1.5% between 1998 and 2005 (P < 0.0001). The rate of ALI was 7.2%. After adjusting for confounders and excluding patients with cirrhosis, the risk of ALI increased with HCV (adjusted odds ratio [aOR] 1.80; 95% confidence interval [CI]: 1.30-2.48), nonalcoholic fatty liver disease (aOR 7.43; 95% CI: 3.30-16.7), alcoholic liver disease (aOR 6.46; 95% CI: 4.53-9.21), and malnutrition (aOR 3.84; 95% CI: 2.61-5.65). HCV was associated with greater risk of progression to severe liver failure (aOR 3.55; 95% CI: 1.88-6.70). Crude mortality was higher in patients with HCV compared to those without HCV (2.1% versus 0.9%, P = 0.01); patients with ALI had an overall mortality of 8.6%. Length of stay was longer in patients with HCV (4.0 versus 2.6 days, P < 0.0001). Admissions with coexistent HCV also incurred two-fold higher hospital charges than those that did not ($21,400 versus $11,400, P < 0.0001). CONCLUSION Our retrospective analysis suggests that patients with HCV may be at increased risk of ALI following AO. These findings warrant further confirmation in prospective studies.
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Affiliation(s)
- Geoffrey C Nguyen
- Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
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Rollason V, Samer C, Piguet V, Dayer P, Desmeules J. Pharmacogenetics of analgesics: toward the individualization of prescription. Pharmacogenomics 2008; 9:905-33. [DOI: 10.2217/14622416.9.7.905] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the µ-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.
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Affiliation(s)
- Victoria Rollason
- Geneva University Hospital, University of Geneva, Clinical Pharmacology & Toxicology, Micheli-du-Crest Street 24, 1211 Geneva 14, Switzerland
| | - Caroline Samer
- Geneva University Hospital, University of Geneva, Clinical Pharmacology & Toxicology, Micheli-du-Crest Street 24, 1211 Geneva 14, Switzerland
| | - Valerie Piguet
- Geneva University Hospital, University of Geneva, Clinical Pharmacology & Toxicology, Micheli-du-Crest Street 24, 1211 Geneva 14, Switzerland
| | - Pierre Dayer
- Geneva University Hospital, University of Geneva, Clinical Pharmacology & Toxicology, Micheli-du-Crest Street 24, 1211 Geneva 14, Switzerland
| | - Jules Desmeules
- Geneva University Hospital, University of Geneva, Clinical Pharmacology & Toxicology, Micheli-du-Crest Street 24, 1211 Geneva 14, Switzerland
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Abstract
Acetaminophen is a commonly used antipyretic and analgesic agent. It is safe when taken at therapeutic doses; however, overdose can lead to serious and even fatal hepatotoxicity. The initial metabolic and biochemical events leading to toxicity have been well described, but the precise mechanism of cell injury and death is unknown. Prompt recognition of overdose, aggressive management, and administration of N-acetylcysteine can minimize hepatotoxicity and prevent liver failure and death. Liver transplantation can be lifesaving for those who develop acute liver failure.
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Affiliation(s)
- Anne M Larson
- Division of Gastroenterology, Hepatology Section, University of Washington, 1959 NE Pacific Street, Box 356174, Seattle, WA 98195-6174, USA.
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Uchimoto T, Itoga S, Nezu M, Sunaga M, Tomonaga T, Nomura F. Role of the Genetic Polymorphisms in the 5'-Flanking Region for Transcriptional Regulation of the Human CYP2E1 Gene. Alcohol Clin Exp Res 2007; 31:S36-42. [PMID: 17331164 DOI: 10.1111/j.1530-0277.2006.00284.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The human cytochrome P-4502E1 (CYP2E1) has been known to be that are associated with alcohol-related diseases and various cancers. Difference in susceptibility in enzyme induction of the CYP2E1 by environmental factors such as ethanol may be associated with the risk of these diseases. In the 5'-flanking region of the human CYP2E1 gene, there were tandem repeat polymorphism (CYP2E1*1C*,1D) and RsaI polymorphism (CYP2E1*5A*,5B), which have been reported to be related to these diseases. Thus, we focused relationship between these polymorphisms and transcriptional regulation. The aim of this study was to determine the role of these polymorphisms for the transcriptional regulation of the human CYP2E1 gene in general transcription and during enzyme induction. METHODS To determine the role of these polymorphisms, various constructs of the 5'-flanking region of the human CYP2E1 gene were prepared and transfected into HeLa cells and HepG2 cells treated or not with pyrazine, a well-known CYP2E1 inducer. RESULTS The transcriptional activity of CYP2E1*1D was higher than that of CYP2E1*1C in HeLa cells. The -1,306 base pairs (bp) construct (-1,306 to +9) increased transcriptional activity compared with the 2.5 kb full-length construct. The suppressive effect of transcriptional activity by deletion of the region including CYP2E1*1C was greater than that by CYP2E1*1D in HeLa cells. The -580 bp construct (-580 to +9) decreased transcriptional activity compared with the -1,306 bp construct. The -1,306 bp construct also showed a similar tendency during pyrazine treatment. CONCLUSIONS The region including the tandem repeat polymorphism was suggested to regulate transcription suppressively. Besides, it was speculated that the transcriptional activity of CYP2E1*1D was higher than that of CYP2E1*1C because transcriptional suppression of CYP2E1*1D was weaker than that of CYP2E1*1C. Also, it was confirmed that the region including RsaI polymorphism was associated with the promotion of transcription.
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Affiliation(s)
- Takayuki Uchimoto
- Department of Molecular Diagnosis (F8), Graduate School of Medicine, Chiba University, Chiba, Japan
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34
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Kozer E, Greenberg R, Zimmerman DR, Berkovitch M. Repeated supratherapeutic doses of paracetamol in children--a literature review and suggested clinical approach. Acta Paediatr 2006; 95:1165-71. [PMID: 16982484 DOI: 10.1080/08035250600580503] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
UNLABELLED The safety of paracetamol when given in the recommended dosage is well documented. However, in recent years there have been many reports of liver failure associated with repeated exposure to supratherapeutic doses of paracetamol. This paper reviews the literature on chronic supratherapeutic paracetamol exposure in children and the different dosing guidelines. Based on which, we suggest the following approach: liver injury secondary to repeated dosing of paracetamol should be considered when a child has received more than 75 mg/kg/d for at least 2 d, or if risk factors for paracetamol toxicity have been identified. Liver transaminases, coagulation factors, and paracetamol serum concentrations should be measured in these children and in symptomatic children with vomiting, right upper quadrant abdominal pain, and jaundice who have taken paracetamol. Treatment with N-acetyl cysteine should be started regardless of paracetamol concentrations if transaminases or INR are elevated. CONCLUSION Liver injury secondary to repeated dosing of paracetamol is rare but may result in severe morbidity and mortality. The cumulative dose of paracetamol should not exceed 75 mg/kg/d. Children treated with higher doses for more than 2 d should be evaluated for possible liver injury and treated with N-acetyl cysteine if evidence of liver injury is found.
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Affiliation(s)
- Eran Kozer
- Pediatric Emergency Medicine, Assaf Harofeh Medical Center, Zerifin, Israel.
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35
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Samer CF, Desmeules JA, Dayer P. Individualizing analgesic prescription. Part II: pharmacogenetics of anti-inflammatory analgesics and co-analgesics. Per Med 2006; 3:271-297. [PMID: 29788658 DOI: 10.2217/17410541.3.3.271] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Caroline Flora Samer
- Geneva University Hospital, Clinical Pharmacology and Toxicology and Multidisciplinary Pain Center, 1211 Geneva 14, Switzerland
| | - Jules Alexandre Desmeules
- Geneva University Hospital, Clinical Pharmacology and Toxicology and Multidisciplinary Pain Center, 1211 Geneva 14, Switzerland
| | - Pierre Dayer
- Geneva University Hospital, Clinical Pharmacology and Toxicology and Multidisciplinary Pain Center, 1211 Geneva 14, Switzerland
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36
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Opiate Addicted Patients: The Misconceptions of Chronic Acetaminophen Ingestion. ADDICTIVE DISORDERS & THEIR TREATMENT 2006. [DOI: 10.1097/01.adt.0000210705.64951.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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37
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Man XB, Tang L, Qiu XH, Yang LQ, Cao HF, Wu MC, Wang HY. Expression of cytochrome P4502E1 gene in hepatocellular carcinoma. World J Gastroenterol 2004; 10:1565-8. [PMID: 15162526 PMCID: PMC4572755 DOI: 10.3748/wjg.v10.i11.1565] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate cytpchrome P4502E1 (CYP2E1) gene expression in occurrence and progression of hepatocellular carcinoma (HCC).
METHODS: The human liver arrayed library was spotted onto the nylon membranes to make cDNA array. Hybridization of cDNA array was performed with labeled probes synthesized from RNA isolated from HCC and adjacent liver tissues. Sprague-Dawley rats were administrated diethylnitrosamine (DENA) to induce HCC. CYP2E1 expression was detected by the method of RT-PCR and Northern blot analysis.
RESULTS: CYP2E1 was found by cDNA array hybridization to express differently between HCC and liver tissues. CYP2E1 only expressed in liver, but did not express in HCC tissues and expressed lowly in cirrhotic tissues. In the progression of cirrhosis and HCC, the expression level of CYP2E1 was gradually decreased and hardly detected until the late stage of HCC.
CONCLUSION: Using arrayed library to make cDNA arrays is an effective method to find differential expression genes. CYP2E1 is a unique gene expressing in liver but did not express in HCC. CYP2E1 expression descended along with the initiation and progression of HCC, which is noteworthy further investigations in its significance in the development of HCC.
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Affiliation(s)
- Xiao-Bo Man
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China
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38
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Nomura F, Itoga S, Uchimoto T, Tomonaga T, Nezu M, Shimada H, Ochiai T. Transcriptional activity of the tandem repeat polymorphism in the 5'-flanking region of the human CYP2E1 gene. Alcohol Clin Exp Res 2003; 27:42S-46S. [PMID: 12960506 DOI: 10.1097/01.alc.0000078612.01626.96] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND There are remarkable interindividual differences in the expression of cytochrome P-4502E1(CYP2E1), which in turn may alter susceptibility to alcohol-related diseases and various cancers. We recently characterized the tandem repeat polymorphism in the 5'-flanking region of the human CYP2E1 gene and found that subjects with the homozygous mutant-type (A4/A4) may be at higher risk of developing esophageal cancer. In this study, we determined how this tandem repeat polymorphism alters transcriptional activities of the human CYP2E1 gene by transfection studies. METHODS The 5'-flanking region (-2,562 base pair to +9 base pair) of the CYP2E1 gene from three individuals of different genotypes (A2/A2, A2/A4, A4/A4) was amplified by polymerase chain reaction. The polymerase chain reaction products placed in front of a luciferase reporter gene were transfected into human hepatoblastoma cells, human esophageal cancer cells, and human uterus cancer cells. Transcriptional activities were determined by the dual-luciferase assay. When indicated, ethanol (50 mM) was included in the culture medium. CYP2E1 messenger RNA levels in peripheral lymphocytes were measured by the real-time reverse transcription-polymerase chain reaction using the LightCycler system. RESULTS The construct including the tandem repeat region exhibited luciferase activities in both A2 and A4 type. It was of note that the activity produced by the A4 allele was significantly greater than that by A2 allele in HeLa cells (p < 0.001). CYP2E1 messenger RNA levels in peripheral blood lymphocytes were comparable between the two genotypes. CONCLUSION Transcriptional activity of the mutant allele of the tandem repeat polymorphism in the 5'-flanking region of the CYP2E1 gene is greater than that of the wild type.
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Affiliation(s)
- Fumio Nomura
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba City, Chiba, Japan.
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39
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Dargan PI, Jones AL. Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case against. Drug Saf 2002; 25:625-32. [PMID: 12137557 DOI: 10.2165/00002018-200225090-00002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The widespread practice of using a lower plasma paracetamol (acetaminophen) concentration threshold for the treatment of paracetamol poisoning in patients with chronic alcoholism has been introduced on the basis of anecdotal case reports. In animals, acute alcohol loading inhibits toxic metabolic activation of paracetamol whilst chronic alcohol administration results in cytochrome P450 (CYP) 2E1 induction with increased toxic metabolic activation of paracetamol by CYP2E1 and increased hepatotoxicity. However, due to species differences in CYP expression, activity and induction, it is not possible extrapolate the results of these animal studies to clinical situations in humans. Isoenzymes are also responsible for the metabolic activation of paracetamol in humans and human studies to date have not convincingly demonstrated increased toxic metabolic activation of paracetamol in patients with chronic alcoholism. Acute alcohol ingestion at the time of a paracetamol overdose is probably protective and the timing and chronicity of alcohol intake is therefore crucial in the interpretation of the effects of alcohol on paracetamol overdose. One of the problems in the interpretation of the literature to date is that insufficient information is available on the timing of alcohol intake in relation to the ingestion of paracetamol. Whilst it is possible that chronic exposure to excessive amounts of alcohol does predispose patients with paracetamol overdose to hepatotoxicity, a critical review of the literature reveals that the evidence to date does not support this. A prospective, controlled study is required. On the basis of the scientific evidence to date, use of the 100 line for patients with chronic alcoholism, in countries where the 200 line represents the standard treatment line, is unjustified.
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Affiliation(s)
- Paul I Dargan
- National Poisons Information Service, London, United Kingdom
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40
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Buckley NA, Srinivasan J. Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case for. Drug Saf 2002; 25:619-24. [PMID: 12137556 DOI: 10.2165/00002018-200225090-00001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
A lower threshold for treatment of paracetamol (acetaminophen) poisoning has been advocated in chronic heavy users of alcohol, based originally on animal studies indicating that chronic alcohol ingestion increased hepatotoxicity. This was attributed to increased production of the toxic metabolite, N-acetyl-p-benzoquinoneimine, by cytochrome P450 (CYP)2E1 induction. The clinical evidence for increased risk is limited to four retrospective studies with potential for referral and reporting bias and conflicting results. No study has specifically addressed the issue of the treatment threshold for acute paracetamol overdose in chronic alcohol users. However, animal studies in multiple species have consistently shown a lower dose of paracetamol is required to produce hepatotoxicity after chronic alcohol use. The knowledge of potential mechanisms has expanded to include effects of other alcohols, such as isopentanol, induction of CYP enzymes other than CYP2E1 and glutathione depletion. There are no convincing reasons or data to suggest these findings do not apply to humans. However, further human toxicokinetic and clinical research is required to quantify the extent of the interaction. Arguments about treating overdoses should not be confused with those about whether there is an alcohol-paracetamol interaction at therapeutic doses. Halving the threshold dose/concentration for treatment is a conservative educated guess that has been widely adopted. In overdose, the potential benefits of treatment at this lower threshold clearly outweigh the minimal risks of acetylcysteine.
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Affiliation(s)
- Nicholas A Buckley
- Department of Clinical Pharmacology & Toxicology, The Canberra Hospital, Woden, Australian Capital Territory, Australia
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41
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Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY 2002; 40:3-20. [PMID: 11990202 DOI: 10.1081/clt-120002882] [Citation(s) in RCA: 208] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The acetaminophen nomogram including its uses and limitations is discussed as well as the development of the N-acetylcysteine protocol. While it has taken many years to elucidate the genetic variability and true multiplicity of the cytochrome P450 "mixed function oxidase system" many publications early on looked at the enzyme system as a single entity. Numerous articles indicated that barbiturates, anticonvulsants, and others could induce "P450" and add to the toxicity of acetaminophen. It rapidly became apparent that just because "P450" was induced when measured as a whole, not all other substrates would have changed metabolic activity. The role of diet and ethanol induction and inhibition on CYP2E1, the enzyme of greatest interest for acetaminophen is multifaceted. The lack of enhancement of acetaminophen toxicity by phenytoin and in fact, the potential for reduction of toxicity with that agent is a good example of the evolution of our knowledge. Further complicating our understanding is the introduction of misleading terms such as "therapeutic misadventure" and other expressions of molecular intent. A critical understanding of the literature makes it clear that therapeutic doses of acetaminophen either alone or in the presence of inducers do not produce toxicity. While the community of clinical toxicologists is small, it needs to be more aggressive in making sure that physicians from other specialties and non-clinical toxicology colleagues understand the significance and implications of this science.
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Affiliation(s)
- Barry H Rumack
- University of Colorado School of Medicine and Rocky Mountain Poison and Drug Center, Denver, USA.
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42
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Abstract
Acetaminophen is widely used in children, because its safety and efficacy are well established. Although the risk of developing toxic reactions to acetaminophen appears to be lower in children than in adults, such reactions occur in pediatric patients from intentional overdoses. Less frequently, acetaminophen toxicity is attributable to unintended inappropriate dosing or the failure to recognize children at increased risk in whom standard acetaminophen doses have been administered. Because the symptoms of acetaminophen intoxication are nonspecific, the diagnosis and treatment of acetaminophen intoxication are more likely to be delayed in unintentional cases of toxicity. This statement describes situations and conditions that may contribute to acetaminophen toxicity not associated with suicidal intentions.
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43
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Tsutsumi M, Ueshima Y, Takase S. Pharmacokinetics of roxatidine acetate in patients with chronic liver disease. J Gastroenterol Hepatol 2001; 16:910-5. [PMID: 11555106 DOI: 10.1046/j.1440-1746.2001.02535.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Patients with liver disease are prone to develop peptic ulceration and often receive H(2)-receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H(2)-receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H(2)-receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease. METHODS Blood samples were obtained from 11 patients with chronic hepatitis, 11 patients with cirrhosis and six healthy subjects. Under fasting conditions, 75 mg of roxatidine acetate was administered orally, and plasma roxatidine levels were determined sequentially from 3 to 12 h. Relationships between pharmacokinetic variables and each parameter related to hepatic functions were also investigated. RESULTS There was no difference in the pharmacokinetic variables and serum levels of roxatidine between chronic hepatitis and healthy controls. In contrast, in cirrhosis, serum roxatidine levels were significantly higher than those in chronic hepatitis and normal control. Half-life, the area under the plasma concentration-time curve and clearance in cirrhosis were also significantly longer, bigger and smaller than those in chronic hepatitis and healthy controls, respectively. The half-life became longer and the clearance became smaller in parallel with the progression of liver disease. Serum levels of hyaluronate and gamma-glutamyl transpeptidase showed a good correlation with half-life, clearance and elimination rate. A good correlation between creatinine clearance and elimination rate was found. CONCLUSION Pharmacokinetics of roxatidine acetate is affected by hepatic function, and the dosage of roxatidine acetate for patients with liver disease, especially cirrhosis, should be modified.
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Affiliation(s)
- M Tsutsumi
- Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
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44
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Liu S, Park J, Schantz S, Stern J, Lazarus P. Elucidation of CYP2E1 5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer. Oral Oncol 2001; 37:437-45. [PMID: 11377232 PMCID: PMC3715306 DOI: 10.1016/s1368-8375(00)00099-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The CYP2E1 gene, whose protein product plays an important role in the metabolism of various carcinogens, exhibits two polymorphisms recognized by the restriction enzymes RsaI and PstI in its transcriptional regulatory region that have been previously implicated in cancer susceptibility. In this study, we have examined these polymorphisms to elucidate CYP2E1 allelic haplotype, examining the prevalence of these CYP2E1 alleles in Caucasians and African Americans and their potential role in risk for oral cancer. In addition to the c1 (RsaI[+]/PstI[-]) and c2 (RsaI[-]/PstI[+]) alleles reported in previous studies, we have identified two new alleles, c3 (RsaI[+]/PstI[+]) and c4 (RsaI[-]/PstI[-]). The prevalence of the c2 and c3 alleles differs between racial groups, with African Americans exhibiting a lower prevalence of the c2 allele (0.003) but a higher prevalence of the c3 allele (0.049) than Caucasians (0.031 for c2 and 0.004 for c3). Of the 570 subjects screened in this study, the c4 allele was observed in one subject, a Caucasian case with the (c4/c4) genotype. A significant increase in the CYP2E1 (c1/c1) genotype was observed in oral cancer cases as compared to frequency-matched controls in subjects who smoked < or =24 pack-years (P=0.033). No association was observed between CYP2E1 genotype and risk for oral cancer in the heavy-smoking group (i.e. > 24 pack-years). Similar trends were observed for both Caucasians and African Americans. These data suggest that the c1 allele may contribute to increased risk for oral cancer.
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Affiliation(s)
- S. Liu
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - J.Y. Park
- H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA
| | - S.P. Schantz
- Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
| | - J.C. Stern
- Department of Otolaryngology, The New York Eye and Ear Infirmary, New York, NY 10003, USA
| | - P. Lazarus
- H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA
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45
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Abstract
It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with 'therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol-alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic. The paracetamol-alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol-ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical. In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion-ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.
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Affiliation(s)
- L F Prescott
- Clinical Pharmacology, University of Edinburgh, Edinburgh, UK
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47
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Abstract
In the literature on AWS, there is repeated emphasis on performing a thorough preanesthesia assessment in patients with suspected chronic alcohol use. Because these patients are difficult to diagnose and to treat in surgical settings if complications arise, a multimodal approach is highly recommended (86). Ideally, AWS should be prevented by adequate prophylaxis. If AWS develops after surgery or trauma, immediate therapy is required. The symptoms of AWS can be controlled using the combination of a benzodiazepine (in Europe, also chlormethiazole) with haloperidol or clonidine. The drug regimens must be individualized and symptom-oriented to treat hallucinations and autonomic signs. Dosages are generally larger than those in detoxification units. Other approaches to modulate the neuroendocrine-immune axis in patients with an increased risk of postoperative infectious complications look promising but await controlled trials.
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Affiliation(s)
- C D Spies
- Klinik für Anaesthesiologie und operative Intensivmedizin, Universitätsklinikum Charité Campus Mitte, Humboldt Universität zu Berlin, Germany.
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48
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Wormhoudt LW, Commandeur JN, Vermeulen NP. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999; 29:59-124. [PMID: 10066160 DOI: 10.1080/10408449991349186] [Citation(s) in RCA: 217] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
In this review, an overview is presented of the current knowledge of genetic polymorphisms of four of the most important enzyme families involved in the metabolism of xenobiotics, that is, the N-acetyltransferase (NAT), cytochrome P450 (P450), glutathione-S-transferase (GST), and microsomal epoxide hydrolase (mEH) enzymes. The emphasis is on two main topics, the molecular genetics of the polymorphisms and the consequences for xenobiotic metabolism and toxicity. Studies are described in which wild-type and mutant alleles of biotransformation enzymes have been expressed in heterologous systems to study the molecular genetics and the metabolism and pharmacological or toxicological effects of xenobiotics. Furthermore, studies are described that have investigated the effects of genetic polymorphisms of biotransformation enzymes on the metabolism of drugs in humans and on the metabolism of genotoxic compounds in vivo as well. The effects of the polymorphisms are highly dependent on the enzyme systems involved and the compounds being metabolized. Several polymorphisms are described that also clearly influence the metabolism and effects of drugs and toxic compounds, in vivo in humans. Future perspectives in studies on genetic polymorphisms of biotransformation enzymes are also discussed. It is concluded that genetic polymorphisms of biotransformation enzymes are in a number of cases a major factor involved in the interindividual variability in xenobiotic metabolism and toxicity. This may lead to interindividual variability in efficacy of drugs and disease susceptibility.
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Affiliation(s)
- L W Wormhoudt
- Leiden Amsterdam Center for Drug Research, Vrije Universiteit, Department of Pharmacochemistry, The Netherlands
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