Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury

Kazuya Maeda; Hajime Takikawa; Mitsuhiko Aiso; Kenji Tsuji; Tatehiro Kagawa; Masaaki Watanabe; Ken Sato; Shotaro Sakisaka; Yoichi Hiasa; Yoshiyuki Takei; Hiromasa Ohira; Etsuko Hashimoto; Minoru Ayada; Tadashi Ikegami; Noriaki Arakawa; Hiroyuki Kusuhara; Yoshiro Saito; Yuichi Sugiyama

doi:10.1111/hepr.13812

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury

Hepatol Res. 2022 Oct;52(10):882-887. doi: 10.1111/hepr.13812. Epub 2022 Aug 5.

Authors

Kazuya Maeda¹, Hajime Takikawa², Mitsuhiko Aiso³, Kenji Tsuji⁴, Tatehiro Kagawa⁵, Masaaki Watanabe⁶, Ken Sato⁷, Shotaro Sakisaka⁸, Yoichi Hiasa⁹, Yoshiyuki Takei¹⁰, Hiromasa Ohira¹¹, Etsuko Hashimoto¹², Minoru Ayada¹³, Tadashi Ikegami¹⁴, Noriaki Arakawa¹⁵, Hiroyuki Kusuhara¹⁶, Yoshiro Saito¹⁵, Yuichi Sugiyama¹⁷

Affiliations

¹ Laboratory of Pharmaceutics, Kitasato University School of Pharmacy, Tokyo, Japan.
² Faculty of Medical Technology, Teikyo University, Tokyo, Japan.
³ Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
⁴ Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Survivors Hospital, Hiroshima, Japan.
⁵ Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.
⁶ Department of Gastroenterology, Kitasato University Medical Center, Kitamoto, Japan.
⁷ Department of Gastroenterology, Gunma University, Maebashi, Japan.
⁸ Department of Gastroenterology, Fukuoka University, Fukuoka, Japan.
⁹ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan.
¹⁰ Department of Gastroenterology, Mie University, Tsu, Japan.
¹¹ Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan.
¹² Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
¹³ Department of Internal Medicine, Heiannomori Memorial Hospital, Hamamatsu, Japan.
¹⁴ Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
¹⁵ Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Japan.
¹⁶ Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
¹⁷ Faculty of Pharmaceutical Sciences, Josai International University, Tokyo, Japan.

PMID: 35834381
DOI: 10.1111/hepr.13812

Abstract

Aim: Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients.

Methods: Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI.

Results: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed.

Conclusions: The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

Keywords: drug-induced liver injury; glutathione S-transferase M1; glutathione S-transferase T1.