Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum γ-glutamyltransferase in valproic acid-treated patients

BackgroundThis study was designed to verify whether the glutathione S-transferase (GST) genotypes affect mild hepatotoxicity in valproic acid (VPA)-treated patients.MethodsThe association between the GSTM1 and GSTT1 genotypes, and the levels of aminotransferases and total bilirubin was retrospectively investigated in 149 Japanese epileptic patients treated with VPA.ResultsThe adjusted odds ratio (OR) of the GSTM1− vs. GSTM1+ genotype and the GSTM1−/GSTT1−vs. GSTM1+/GSTT1+ genotypes for γ-glutamyltransferase (GGT) increase over the upper limit of normal were 2.8 [95% confidence interval (CI): 1.1–7.2] and 6.5 (95% CI: 1.5–28.0), respectively. The GSTT1 genotypes alone did not significantly affect the liver function tests. The alanine aminotransferase, aspartate aminotransferase and (γ-glutamyltransferase) GGT levels in patients treated with VPA > 6 months were significantly higher in the GSTM1− than GSTM1+ genotype. The GGT levels were significantly higher in the older subjects receiving polytherapy, and the effects of the polytherapy and age were greater in the GSTM1− genotype.ConclusionsThe GSTM1− and GSTM1−/GSTT1− genotypes may be a genetic risk factor for the increase of GGT in VPA-treated patients. However, it was not possible to clarify whether the GGT increase was caused by VPA-induced hepatotoxicity or not.