Abstract
Glutathione S-transferase (GST) is a major phase II drug-metabolizing enzyme. Several isoforms of human GST as well as different GST genetic polymorphisms are known, but limited data exists concerning the relationship between GST polymorphisms and GST activity using 1-chloro-2,4-dinitrobenzene in human liver. To resolve this query, we analyzed the genetic polymorphisms of four main GST isoforms [GST mu 1 (GSTM1), GST theta 1 (GSTT1), GST alpha 1 (GSTA1), GST pi 1 (GSTP1)] and measured hepatic GST activity isolated from the same patients. We found that GSTM1 null individuals have significantly lower (P=0.0082) GST activity compared with GSTM1 positive individuals. No significant changes in GST activity were observed in individuals with GSTT1, GSTA1, and GSTP1 genotypes. Interestingly, the levels of GST activity exhibited were similar when compared with GSTA1*A/*A and GSTA1*A/*B, and GSTP1*A/*A and GSTP1*A/*B, respectively, if the genotype was GSTM1 null. Therefore, the genotypes of GSTA1*A/*B and GSTP1*A/*B individuals do not significantly affect the level of hepatic GST activity. An examination of the correlation between GST mRNA expression and GST activity subsequently revealed a significant correlation between GSTM1 mRNA levels and GST activity (r=0.626, P=0.007). These data are expected to facilitate research on the prediction of efficacy and safety of GSTM1 null-mediated drug metabolism and may establish whether genetic polymorphisms of the GST gene, specifically GSTM1, can act as a biomarker.
