NAT2*6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

doi:10.3748/wjg.v13.i45.6003

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World Journal of Gastroenterology

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Clinical Research

World J Gastroenterol. Dec 7, 2007; 13(45): 6003-6008
Published online Dec 7, 2007. doi: 10.3748/wjg.v13.i45.6003

NAT2*6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

Norihide Higuchi, Naoko Tahara, Katsunori Yanagihara, Kiyoyasu Fukushima, Naofumi Suyama, Yuichi Inoue, Yoshitsugu Miyazaki, Tsutomu Kobayashi, Koh-ichiro Yoshiura, Norio Niikawa, Kazuhiro Tsukamoto, Shigeru Kohno, Yohei Mizuta, Katsuhisa Omagari, Saburou Shikuwa, Hajime Isomoto, Chun-Yang Wen

Norihide Higuchi, Naoko Tahara, Tsutomu Kobayashi, Kazuhiro Tsukamoto, Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Katsunori Yanagihara, Yoshitsugu Miyazaki, Hajime Isomoto, Saburou Shikuwa, Katsuhisa Omagari, Yohei Mizuta, Shigeru Kohno, Second Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1, Nagasaki 852-8501, Japan

Kiyoyasu Fukushima, Division of Internal Medicine, Japanese Red Cross Nagasaki Genbaku Isahaya Hospital, Isahaya 859-0497, Japan

Naofumi Suyama, Department of Internal Medicine, Nagasaki Municipal Medical Center, Nagasaki 852-8012, Japan

Yuichi Inoue, Department of Internal Medicine, Isahaya Health Insurance General Hospital, Isahaya 854-8501, Japan

Koh-ichiro Yoshiura, Norio Niikawa, Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-12-4, Nagasaki 852-8523, Japan

Koh-ichiro Yoshiura, Norio Niikawa, Kazuhiro Tsukamoto, SORST, JST, Kawaguchi, Japan

Chun-Yang Wen, Department of Digestive Disease Center, Beihua University, Jilin 132013, Jilin Province, China

Author contributions: All authors contributed equally to the work.

Supported by Grant-in-Aid for Scientific Research (Category B, No. 18390168) for K Tsukamoto by the Ministry of Education, Culture, Sports, Science and Technology of Japan

Correspondence to: Professor Kazuhiro Tsukamoto, Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ktsuka@nagasaki-u.ac.jp

Telephone: +81-95-8192447 Fax: +81-95-8192895

Received: December 18, 2006
Revised: September 3, 2007
Accepted: October 25, 2007
Published online: December 7, 2007

Abstract

AIM: To investigate an association between N-acetyltransferase 2 (NAT2)-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients.

METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.

RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A, was significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia.

CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.

Keywords: Tuberculosis; Anti-tuberculosis drugs; Drug-induced hepatotoxicity; NAT2-haplotype; DNA-based diagnosis