Polymorphism of human mu class glutathione transferases

Abstract

A combined database mining approach was used to detect polymorphisms in the mu class glutathione-S-transferase (GST) genes. Although a large number of potential polymorphisms were detected in the five genes that comprise the Mu class GSTs using sequence alignment programs and by searching single nucleotide polymorphism databases, the majority were not validated or detected in three major ethnic populations (African, Southern Chinese and Australian European). Two new polymorphisms were detected and characterized in the GSTM3 gene. A rare pG147W substitution was detected only in the Southern Chinese subjects. A more common pV224I substitution was found in each of the ethnic groups studied, and significant differences in allele frequencies were observed between each group. These two polymorphisms can combine to form four distinct haplotypes (GSTM3A [p.G147;V224], GSTM3C [p.G147;I224], GSTM3D [p.W147;V224], GSTM3E [p.W147;I224]). The four isoforms were expressed in Escherichia coli and characterized enzymatically with several substrates including 1-chloro-2,4-dinitrobenzene (CDNB), cumene hydroperoxide and t-nonenal. GSTM3-3 containing the variant p.W147 residue tended to show diminished specific activity and catalytic efficiency with CDNB. In contrast, GSTM3-3 containing the variant p.I224 residue tended to show increased specific activity and catalytic efficiency with CDNB. Interactions between the different p.147 and p.224 residues were also observed, with the GSTM3C isoform exhibiting the greatest activity with each substrate, and GSTM3E the lowest. These functional polymorphisms may play a significant role in modulating the ability of GSTM3-3 to metabolize substrates such as the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea.