Clinical Research
Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
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, Chun-Yang Wen, Hajime Isomoto, Saburou Shikuwa, Katsuhisa Omagari, Yohei Mizuta, Shigeru Kohno, Kazuhiro Tsukamoto
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