|
1
|
Kirkland D, Kovochich M, More SL, Murray FJ, Monnot AD, Miller JV, Jaeschke H, Jacobson-Kram D, Deore M, Pitchaiyan SK, Unice K, Eichenbaum G. A comprehensive weight of evidence assessment of published acetaminophen genotoxicity data: Implications for its carcinogenic hazard potential. Regul Toxicol Pharmacol 2021; 122:104892. [PMID: 33592196 DOI: 10.1016/j.yrtph.2021.104892] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 02/03/2021] [Accepted: 02/09/2021] [Indexed: 11/17/2022]
Abstract
In 2019, the California Office of Environmental Health Hazard Assessment initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of its genotoxicity. The objective of this analysis was to inform this review process with a weight-of-evidence assessment of more than 65 acetaminophen genetic toxicology studies that are of widely varying quality and conformance to accepted standards and relevance to humans. In these studies, acetaminophen showed no evidence of induction of point or gene mutations in bacterial and mammalian cell systems or in in vivo studies. In reliable, well-controlled test systems, clastogenic effects were only observed in unstable, p53-deficient cell systems or at toxic and/or excessively high concentrations that adversely affect cellular processes (e.g., mitochondrial respiration) and cause cytotoxicity. Across the studies, there was no clear evidence that acetaminophen causes DNA damage in the absence of toxicity. In well-controlled clinical studies, there was no meaningful evidence of chromosomal damage. Based on this weight-of-evidence assessment, acetaminophen overwhelmingly produces negative results (i.e., is not a genotoxic hazard) in reliable, robust high-weight studies. Its mode of action produces cytotoxic effects before it can induce the stable, genetic damage that would be indicative of a genotoxic or carcinogenic hazard.
Collapse
|
|
2
|
Mullins ME, Yeager LH, Freeman WE. Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review. Clin Toxicol (Phila) 2020; 58:1284-1296. [PMID: 32762579 DOI: 10.1080/15563650.2020.1798979] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity. OBJECTIVE We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit. METHODS We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO. RESULTS We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole.Cimetidine: There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning.Fomepizole: There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated.Calmangafodipir: Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway. CONCLUSIONS The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.
Collapse
Affiliation(s)
- Michael E Mullins
- Section of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Lauren H Yeager
- School of Medicine, Bernard Becker Medical Library Medicine, Washington University, St. Louis, Missouri, USA
| | - William E Freeman
- Section of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| |
Collapse
|
|
3
|
Jeyamogan S, Khan NA, Anwar A, Shah MR, Siddiqui R. Cytotoxic effects of Benzodioxane, Naphthalene diimide, Porphyrin and Acetamol derivatives on HeLa cells. SAGE Open Med 2018; 6:2050312118781962. [PMID: 30034805 PMCID: PMC6048657 DOI: 10.1177/2050312118781962] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 05/17/2018] [Indexed: 11/17/2022] Open
Abstract
Objectives: To synthesize novel compounds belonging to Benzodioxane, Naphthalene diimide,
Aminophenol derivatives and Porphyrin classes and test their potential
anticancer properties. Methods: Several compounds were synthesized and their molecular identity was confirmed
using nuclear magnetic resonance. Potential anticancer properties were
determined using cytopathogenicity assays and growth inhibition assays using
cervical cancer cells (HeLa). Cells were incubated with different
concentrations of compounds belonging to Benzodioxane, Naphthalene diimide,
Aminophenol derivatives and Porphyrins and effects were determined. HeLa
cells cytopathogenicity was determined by measuring lactate dehydrogenase
release using cytotoxicity detection assay. Growth inhibition assays were
performed by incubating 50% semi-confluent HeLa cells with Benzodioxane,
Naphthalene diimide, Aminophenol derivatives and Porphyrin compounds and
HeLa cell proliferation was observed. Growth inhibition and host cell death
were compared in the presence and absence of drugs. Results: Cytopathogenicity assays showed that the selected compounds were cytotoxic
against HeLa cells, killing up to 90% of cells. Growth inhibition assays
exhibited 100% growth inhibition. These effects are likely via oxidative
stress, production of reactive oxygen species, changes in cytosolic and
intracellular calcium/adenine nucleotide homeostasis, inhibition of
ribonucleotide reductase/cyclooxygenase and/or glutathione depletion. Conclusions: Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrins
exhibited potent anticancer properties. These findings are promising and
should pave the way in the rationale development of anticancer drugs. Using
different cancer cell lines, future studies will determine their potential
as anti-tumour agents as well as their precise molecular mode of action.
Collapse
Affiliation(s)
- Shareni Jeyamogan
- Department of Biological Sciences, School of Science and Technology, Sunway University, Subang Jaya, Malaysia
| | - Naveed Ahmed Khan
- Department of Biological Sciences, School of Science and Technology, Sunway University, Subang Jaya, Malaysia
| | - Ayaz Anwar
- International Center for Chemical and Biological Sciences, Hussain Ebrahim Jamal Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
| | - Muhammad Raza Shah
- International Center for Chemical and Biological Sciences, Hussain Ebrahim Jamal Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
| | - Ruqaiyyah Siddiqui
- Department of Biological Sciences, School of Science and Technology, Sunway University, Subang Jaya, Malaysia
| |
Collapse
|
|
4
|
Josephine A, Veena CK, Amudha G, Preetha SP, Varalakshmi P. Protective role of sulphated polysaccharides in abating the hyperlipidemic nephropathy provoked by cyclosporine A. Arch Toxicol 2007; 81:371-9. [PMID: 17019561 DOI: 10.1007/s00204-006-0151-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2006] [Accepted: 08/28/2006] [Indexed: 10/24/2022]
Abstract
Cyclosporine A (CsA)-induced nephrotoxicity hampers the immense therapeutic potential of such a powerful immunosuppressant. The present study was conducted with an aim to explicate the contribution of sulphated polysaccharides (SPS) in abating the lipid abnormalities induced by CsA in the rat kidney. Hyperlipidemia associated with nephrotic syndrome may play a role in the worsening of renal function. Male albino Wistar rats sorted into four groups were used for the study. CsA was given at a dose of 25 mg/kg body weight, orally for 21 days. Significant alterations in the lipid profile as well an increase in the activity of cholesterol ester synthase, coupled with a decrease in cholesterol ester hydrolase and lipoprotein lipase enzyme activities were noted in the plasma and kidneys of CsA-administered rats. A marked increase in the lipoprotein fractions, low-density lipoprotein (LDL) and very low density lipoprotein (VLDL), along with a decrease in the HDL level were found in CsA-administered rats. The degree of nephrotoxicity allied with lipid discrepancies was evident from augmented urinary excretion of urea, uric acid and creatinine. Further, an enhanced susceptibility of the apo B-containing lipoproteins (LDL + VLDL) to oxidation in vitro, induced by copper ions was also found in the plasma of CsA given groups. While SPS co-treated groups (5 mg/kg body weight, subcutaneously) revealed a normalized lipid profile and lipid metabolizing enzymes, the supplementation of SPS also brought back the elevated urinary constituents close to that of the controls and substantially minimized the oxidative changes. With these observations, it may be concluded herein that SPS may be an ideal choice as a renoprotective and hypolipidemic agent against CsA-induced hyperlipidemic nephropathy.
Collapse
Affiliation(s)
- Anthony Josephine
- Department of Medical Biochemistry, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, India
| | | | | | | | | |
Collapse
|
|
5
|
Ishida Y, Kondo T, Kimura A, Tsuneyama K, Takayasu T, Mukaida N. Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury. Eur J Immunol 2006; 36:1028-1038. [PMID: 16552707 DOI: 10.1002/eji.200535261] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Neutrophils and macrophages infiltrate after acetaminophen (APAP)-induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG-treated wild-type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 h after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All anti-granulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)-deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAP-induced liver injury. However, APAP caused more exaggerated liver injury in CXCR2-deficient mice with reduced macrophage infiltration and HO-1 gene expression, compared with neutropenic WT mice. An HO-1 inhibitor, tin-protoporphyrin-IX, significantly increased APAP-induced mortality, implicating HO-1 as a protective molecule for APAP-induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury.
Collapse
Affiliation(s)
- Yuko Ishida
- Division of Molecular Bioregulation, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | | | | | | | | | | |
Collapse
|
|
6
|
Yu WF, Yang LQ, Zhou MT, Liu ZQ, Li Q. Ca 2+ cytochemical changes of hepatotoxicity caused by halothane and sevoflurane in enzyme-induced hypoxic rats. World J Gastroenterol 2005; 11:5025-8. [PMID: 16124059 PMCID: PMC4321923 DOI: 10.3748/wjg.v11.i32.5025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigat the relation between hepatotoxicity of halothane and sevoflurane and altered hepatic calcium homeostasis in enzyme-induced hypoxic rats.
METHODS: Forty-eight rats were pretreated with phen-obarbital and randomly divided into six groups (eight in each group) and exposed to O2/ N2/1.2 MAC anesthetics for 1 h: normal control (NC), 21% O2/79% N2; hypoxic control (HC), 14% O2/86%N2; normal sevoflurane (NS), 21% O2/ N2/1.2MAC sevoflurane; hypoxic sevoflurane (HS), 14% O2/ N2/1.2MAC sevoflurane; normal halothane (NH)21%O2/79%N2/1.2MAC halothane; hypoxic halothane (HH), 14% O2/N2/1.2MAC halothane. Liver specimens and blood were taken 24 h after exposure to calcium and determined by EDX microanalysis.
RESULTS: The liver of all rats given halothane (14% O2) had extensive centrilobular necrosis and denaturation. Morphologic damage was accompanied with an increase in serum glutamic pyruvic transminase. In groups NH and HH, more calcium was precipitated in cytoplasm and mitochondria.
CONCLUSION: These results suggest that halothane increases cytosolic Ca2+ concentration in hepatocytes. Elevation in Ca2+ concentration is implicated in the mechanism of halothane-induced hepatotoxicity. sevoflurane is less effective in affecting hepatic calcium homeostasis than halothane.
Collapse
Affiliation(s)
- Wei-Feng Yu
- Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200438, China.
| | | | | | | | | |
Collapse
|
|
7
|
Raghavendran HRB, Sathivel A, Devaki T. Effect of Sargassum polycystum (Phaeophyceae)-sulphated polysaccharide extract against acetaminophen-induced hyperlipidemia during toxic hepatitis in experimental rats. Mol Cell Biochem 2005; 276:89-96. [PMID: 16132689 DOI: 10.1007/s11010-005-3194-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2005] [Accepted: 03/04/2005] [Indexed: 10/25/2022]
Abstract
The effect of Sargassum polycystum crude extract on lipid metabolism was examined against acetaminophen-induced (800 mg/kg body wt., intraperitoneally) hyperlipidemia during toxic hepatitis in experimental rats. The animals intoxicated with acetaminophen showed significant elevation in the levels of cholesterol, triglycerides and free fatty acid in both serum and liver tissue. The levels of tissue total lipids and serum LDL-cholesterol were also elevated with depleted levels of serum HDL-cholesterol and tissue phospholipid. The acetaminophen-induced animals showed significant alterations in the activities of lipid metabolizing enzymes serum lecithin cholesterol acyl transferase (LCAT) and hepatic triglyceride lipase (HTGL). The levels of liver tissue fatty acids (saturated, mono and polyunsaturated) such as palmitic acid, stearic acid, oleic acid, linoleic acid, arachidonic acid and linolenic acid monitored by gas chromatography were considerably altered in acetaminophen intoxicated animals when compared with control animals. The prior oral administration of Sargassum polycystum (200 mg/kg body wt./day for a period of 15 days) crude extract showed considerable prevention in the severe disturbances of lipid profile and metabolizing enzymes triggered by acetaminophen during hepatic injury. Liver histology also showed convincing supportive evidence regarding their protective nature against fatty changes induced during acetaminophen intoxication. Thus the present study indicates that the protective nature of Sargassum polycystum extract may be due to the presence of active compounds possessing antilipemic property against acetaminophen challenge.
Collapse
|
|
8
|
Holownia A, Braszko JJ. Acetaminophen alters microsomal ryanodine Ca2+ channel in HepG2 cells overexpressing CYP2E1. Biochem Pharmacol 2004; 68:513-21. [PMID: 15242817 DOI: 10.1016/j.bcp.2004.04.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2004] [Accepted: 04/13/2004] [Indexed: 11/29/2022]
Abstract
Acetaminophen hepatotoxicity is mediated by an initial metabolic activation and covalent binding of drug metabolites to liver proteins. Acetaminophen metabolites have been shown to affect rat liver microsomal Ca2+ stores, but the mechanism is not well understood. The aim of the current work was to find out if the metabolism of acetaminophen by CYP2E1 affects ryanodine-sensitive Ca2+ stores in the endoplasmic reticulum of transduced HepG2 cells. Five millimoles acetaminophen decreased proliferation of CYP2E1-overexpressing HepG2 cells, increased cytosolic Ca2+ levels and produced significant cytotoxicity, while only little, mostly anti-proliferative effects were found in HepG2 cells lacking CYP2E1. CYP2E1 inhibitor-4-methylpyrazole decreased drug cytotoxicity in transduced cells and normalized elevated Ca2+ levels. Acetaminophen cytotoxicity was significantly higher in CYP2E1 expressing cells with depleted glutathione. In the cells engineered to overexpress CYP2E1, an increased [3H]ryanodine affinity (by 45%) and increased ligand maximal binding to ryanodine receptors (by 64%) was observed, most probably due to increased association rate of [3H]ryanodine. Ca2+ loading was decreased by about 53% in microsomal fractions isolated from transduced cells treated with acetaminophen and by 92% in glutathione depleted transfected cells treated with the drug. Ca2+/Mg2+-ATPase activity was unchanged in all microsomal fractions. Such effects were not observed in cells lacking CYP2E1. Our results confirm significant role of CYP2E1 in metabolic activation of acetaminophen and indicate that ryanodine receptors located in the liver endoplasmic reticulum are sensitive targets for acetaminophen metabolites.
Collapse
Affiliation(s)
- Adam Holownia
- Department of Clinical Pharmacology, Medical Academy of Bialystok, Waszyngtona 15A, 15-274 Bialystok, Poland.
| | | |
Collapse
|
|
9
|
van Dijk TH, Boer TS, Havinga R, Stellaard F, Kuipers F, Reijngoud DJ. Quantification of hepatic carbohydrate metabolism in conscious mice using serial blood and urine spots. Anal Biochem 2003; 322:1-13. [PMID: 14705774 DOI: 10.1016/j.ab.2003.07.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2003] [Indexed: 10/27/2022]
Abstract
In vivo studies of hepatic carbohydrate metabolism in (genetically modified) conscious mice are hampered by limitations of blood and urine sample sizes. We developed and validated methods to quantify stable isotope dilution and incorporation in small blood and urine samples spotted onto filter paper. Blood glucose and urinary paracetamol-glucuronic acid were extracted from filter paper spots reproducibly and with high yield. Fractional isotopomer distributions of glucose and paracetamol-glucuronic acid when extracted from filter paper spots were almost identical to those isolated from the original body fluids. Rates of infusion of labeled compounds could be adjusted without perturbing hepatic glucose metabolism. This approach was used in mice to find the optimal metabolic condition for the study of hepatic carbohydrate metabolism. In fed mice, no isotopic steady state was observed during a 6-h label-infusion experiment. In 9-h-fasted mice, isotopic steady state was reached after 3 h of label infusion and important parameters in hepatic glucose metabolism could be calculated. The rate of de novo glucose-6-phosphate synthesis was 143 +/- 17 micromol kg(-1) min(-1) and partitioning to plasma glucose was 79.0 +/- 5.2%. In 24-h-fasted mice, abrupt changes were noticed in whole body and in hepatic glucose metabolism at the end of the experiment.
Collapse
Affiliation(s)
- Theo H van Dijk
- Laboratory of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
| | | | | | | | | | | |
Collapse
|
|
10
|
Vater Y, Dembo G, Levy A, Hunter C, Martay K. Adjunct drugs in liver transplantation. ACTA ACUST UNITED AC 2002. [DOI: 10.1053/sane.2002.34196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
|
|
11
|
Bergman K, Müller L, Teigen SW. Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view. Mutat Res 1996; 349:263-88. [PMID: 8600357 DOI: 10.1016/0027-5107(95)00185-9] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The publication of several studies reporting genotoxic effects of paracetamol, one of the world's most popular over-the-counter drugs, has raised the question of regulatory action. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. There are, however, published data giving clear evidence that paracetamol causes chromosomal damage in vitro in mammalian cells at high concentrations and indicating that similar effects occur in vivo at high dosages. Available data point to three possible mechanisms of paracetamol-induced genotoxicity: (1) inhibition of ribonucleotide reductase; (2) increase in cytosolic and intranuclear Ca2+ levels; (3) DNA damage caused by NAPQI after glutathione depletion. All mechanisms involve dose thresholds. Studies of the relationship between genotoxicity and toxic effects in the rat (induction of micronuclei in rat bone marrow including dose-response relationship, biotransformation of paracetamol at different dosages, concomitant toxicity and biochemical markers) have recently been completed. These studies, which employed doses ranging from the dose resulting in human therapeutic peak plasma levels to highly toxic doses, give convincing evidence that genotoxic effects of paracetamol appear only at dosages inducing pronounced liver and bone marrow toxicity and that the threshold level for genotoxicity is not reached at therapeutic dosage. Reliable studies on the ability of paracetamol to affect germ cell DNA are not available. However, based on the amount of drug likely to reach germ cells and the evidence of thresholds, paracetamol is not expected to cause heritable damage in man. Various old and poorly designed long-term studies of paracetamol in the mouse and rat have given equivocal results. A few of these studies showed increased incidence of liver and bladder tumours at hepatotoxic doses. National Toxicology Program (U.S.A.) feeding studies have shown that paracetamol is non-carcinogenic when given at non-hepatotoxic doses up to 300 mg/kg/d to the rat and up to 1000 mg/kg/d to the mouse. Taking into account the knowledge of the hepatotoxicity and metabolism of paracetamol and the existence of thresholds for its genotoxicity, the animal studies do not indicate a carcinogenic potential at non-hepatotoxic dose levels. Based on this updated assessment of the genotoxicity and carcinogenicity of paracetamol, it is concluded that there is no need for regulatory action.
Collapse
Affiliation(s)
- K Bergman
- Medical Products Agency, Uppsala, Sweden
| | | | | |
Collapse
|