HUMAN GLUTATHIONE-S-TRANSFERASE P1 POLYMORPHISMS - RELATIONSHIP TO LUNG-TISSUE ENZYME-ACTIVITY AND POPULATION FREQUENCY-DISTRIBUTION

The association between glutathione S-transferase (GST) activity as me asured by 1-chloro-2,4-dinitrobenzene (CDNB) conjugation and genotype at exon 5 and exon 6 of the human GSTP1 gene was investigated in norma l lung tissue obtained from 34 surgical patients. These samples were g enotyped for previously identified polymorphisms in exon 5 (Ile105Val) and exon 6 (Ala114Val) by PCR-RFLP and direct sequencing. GST enzyme activity was significantly lower among individuals with the 105 Val al lele. Homozygous Ile/Ile samples (n = 18) had a mean cytosolic CDNB co njugating activity of 74.9 +/- 3.8 mnol/mg per min; heterozygotes (n = 13) had a mean specific activity of 62.1 +/- 4.2 nmol/mg per min and homozygous Val/Val (n = 3) had a mean specific activity of 52.5 +/- 4. 5 nmol/mg mg per min. The CDNB conjugating activity measured for the I le/Ile genotype group was significantly different from that observed i n the Ile/Val group (P = 0.03), and from Ile/Val and Val/Val genotypes combined (P = 0.009). Mean GST activity values mere consistently lowe r in individuals with genotypes containing the 105 valine allele, rega rdless of smoking exposure. Genotypes at codon 114 were also assessed but the mean GST activity was not significantly lower in individuals w ith the 114 valine allele. A new haplotype, present in two samples who were homozygous 105Ile and had a 114Val, was identified and proposed as GSTP1D. Frequencies of the exon 5 and exon 6 polymorphisms were de termined in samples obtained from European-Americans, African-American s and Taiwanese. The differences observed were highly significant sugg esting the possibility of GSTP1 genotype-associated, ethnic difference s in cancer susceptibility and chemotherapeutic response.