Glutathione‐S‐Transferase (GST) M1 Null Genotype and Combined GSTM1 and GSTT1 Null Genotypes as a Risk Factor for Alcoholic Mild Liver Dysfunction

To the editor: In Clinical Pharmacology and Therapeutics, Watanabe et al. reported the frequency of the combined null genotypes for glutathione-Stransferase m 1 (GSTM1) and y 1 (GSTT1) was significantly higher in cases with troglitazone-induced idiosyncratic liver injury than the troglitazone-treated controls (odds ratio, 3.6). Although the results have not yet verified to induce any drug-induced liver dysfunction, Kaplowitz recently suggested that a phenomenon common to a rare idiosyncratic reaction tends to be the background of more frequent, but mild asymptomatic liver injury. We therefore investigated whether each genotype or the combined GSTM1 and GSTT1 null genotypes could influence mild liver dysfunction in Japanese individuals. After obtaining the approval of the institutional ethics committees and individual informed consent from all subjects, we determined the GSTM1 and GSTT1 genotypes in 215 (148 men and 67 women) participants in a 2-day health screening program at the Japanese Red Cross Kumamoto Health Care Center (Kumamoto, Japan) by the method of Watanabe et al. The characteristics of the subjects were as follows: age (mean7SD, 52.278.2 years); body mass index (23.773.1); alanine aminotransferase (25.3716.5 IU/l (9–168 IU/l)); aspartate aminotransferase (23.778.3 IU/l (12–83 IU/l)); non-drinkers who consume nil or a small amount of alcohol less than once a week, 89 cases; drinkers who consume alcohol o30 g/day, 83 cases; X30 and o60/day, 20 cases; once X60 g/day, 23 cases. All participants were examined for the presence of hepatitis B surface antigens and hepatitis C virus antibody and those with positive results were excluded from the analysis. A doctor, a dietitian, a nurse, and/or a clinical pharmacologist collected the information regarding alcohol use and ruled out other causes of abnormal liver function, such as occupational exposures and drugs, by using a structured questionnaire and from face-to-face interviews. The frequencies of the GSTM1 null and GSTT1 null genotypes were 56.7 and 44.2%, respectively. Table 1 shows the distribution of the GSTM1 and GSTT1 genotypes in the subjects with a normal or elevated transaminase level above upper limits of normal. There were significant associations between the GSTM1 null genotype and a mild elevation of alanine aminotransferase in all subjects and in drinkers, between the combination of GSTM1 and GSTT1 genotypes and the elevation of alanine aminotransferase in all subjects and in drinkers and of aspartate aminotransferase in drinkers, and between the combined GSTM1 and GSTT1 null genotypes and the elevation of aspartate aminotransferase in all subjects (Table 1); however, no such association was found in non-drinkers (data not shown). The influence of the genotypes were also examined with multiple liver function tests, and significant associations were observed between the GSTT1 null genotype and the combined GSTM1 and GSTT1 null genotypes and a mild elevation of zinc sulfate turbidity test in all subjects, and the median levels of lactate dehydrogenase and choline esterase were significantly higher in GSTM1 null genotypes in all subjects and in drinkers (data not shown). These results suggested that the combined GSTM1 and GSTT1 null genotypes might therefore be a risk factor for alcoholic mild liver dysfunction. The combined null genotypes have also been reported to be a risk factor for advanced alcoholic liver disease. The phenotypes of idiosyncratic drug-induced liver injury and alcohol-induced liver injury are different, but some pathogeneses may be common to both. Accumulating evidence suggests that oxidative stress plays a major role in liver injury regardless of the etiology or severity. Glutathione-S-transferases detoxify electrophilic xenobiotics and inactivate a variety of endogenous by-products of oxidative stress, and GSTM1 and GSTT1 are predominantly expressed in the liver. Further methodical studies are definitely needed to clarify the role of glutathione-S-transferases and the effect of the combined null genotypes in drugand alcohol-induced liver injury; however, the common features of our results and those of Watanabe et al. are thus considered to be worthy of note.