Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression

The patterns of expression of glutathione S-transferases A1 and A2 in human liver (hGSTA1 and hGSTA2, respectively) are highly variable, notably in th e ratio of hGSTA1/hGSTA2. We investigated if this variation had a genetic b asis by sequencing the proximal promoters (-721 to -1 nucleotides) of hGSTA 1 and hGSTA2, using 55 samples of human liver that exemplified the variabil ity of hGSTA1 and hGSTA2 expression. Variants were found in the hGSTA1 gene : -631T or G, -567T, -69C, -52G, designated as hGSTA1*A; and -631 G, -567G, -69T, -52A, designated as hGSTA1*B. Genotyping for the substitution -69C > T by polymerase chain reaction restriction fragment length polymorphism (P CR-RFLP), showed that the polymorphism was widespread in Caucasians, Africa n Americans and Hispanics, and that it appeared to conform to allelic varia tion. Constructs consisting of the proximal promoters of hGSTA1*A, hGSTA1*B or hGSTA2, with luciferase as a reporter gene, showed differential express ion when transfected into HepG2 cells: hGSTA1*A hGSTA2 > hGSTA1*B. Similarl y, mean levels of hGSTA1 protein expression in liver cytosols decreased sig nificantly according to genotype: hGSTA1*A > hGSTA1-heterozygous > hGSTA1*B . Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype. Consequently, the ratio of GSTA1/GSTA2 was highly hGSTA 1 allele-specific. Because the polymorphism in hGSTA1 correlates with hGSTA 1 and hGSTA2 expression in liver, and hGSTA1-1 and hGSTA2-2 exhibit differe ntial catalysis of the detoxification of carcinogen metabolites and chemoth erapeutics, the polymorphism is expected to be of significance for individu al risk of cancer or individual response to chemotherapeutic agents. Pharma cogenetics 11:663-669 (C) 2001 Lippincott Williams & Wilkins.