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Quantitative Analysis of Interindividual Variation of Glutathione S-Transferase Expression in Human Pancreas and the Ambiguity of Correlating Genotype with Phenotype¹

Divisions of Molecular Epidemiology [B. F. C., F. F. K.], and Biochemical Toxicology [D. R. D., M. I. C.], National Center for Toxicological Research, Jefferson, Arkansas 72079; Division of Epidemiology, University of Minnesota, Minneapolis, Minnesota 55454 [K. E. A.]; Department of Surgery, University of Arkansas for Medical Sciences and Arkansas Cancer Research Center, Little Rock, Arkansas 72205 [N.P.L.]: and Surgery Services, Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205 [N. P. L.]

Analysis of glutathione S-transferases (GSTs) of the alpha, mu, and pi classes by reverse-phase high-performance liquid chromatography and electrospray-ionization mass spectrometry in 43 samples of normal human pancreas demonstrated a wide variation in expression of subunits P1, A1, A2, A4, M1, M2, and M3 and the presence of a novel form designated GST "A5." GSTA2 consisted of three forms that were differentially expressed between individuals in a manner consistent with allelic polymorphism at the hGSTA2 locus. Expression, in terms of µg GST subunit/mg cytosolic protein, varied by 6–15-fold for subunits P1, A2, and M3 and 17–30-fold in the case of GSTs A1 and M2. Less consistently expressed were GSTs M1a, M1b, A4, and A5. Among these, GSTM1 expression (excluding M1-null samples) varied 12-fold between samples, whereas GST A4 and A5 expression varied 50–100-fold between samples, well beyond the range of other subunits, suggesting that their expression is highly inducible. Linear correlations (P < 0.001–0.003) existed between levels of the most consistently expressed GST, GSTP1, and total GSTs, GSTA2 and M3, and in GSTM1-positive samples, between GSTM1, M3, and P1. The correlation between GST subunits P1 and M3 was bimodal according to M1 genotype, reflecting the presence of the regulatory element in hGSTM3*B that is linked with the hGSTM1*A genotype. It is concluded that although a degree of regulation of expression of GSTs occurs in human pancreas, the variability of phenotype is high and might obscure the effects of genetic polymorphisms on individual cancer susceptibility. Interindividual variation of GST expression is, therefore, a factor that should be taken account of in epidemiological studies.

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