Quantitative analysis of interindividual variation of glutathione S-transferase expression in human pancreas and the ambiguity of correlating genotype with phenotype

Analysis of glutathione S-transferases (GSTs) of the alpha, mu, and pi clas ses by reverse-phase high-performance liquid chromatography and electrospra y-ionization mass spectrometry in 43 samples of normal human pancreas demon strated a wide variation in expression of subunits PI, A1, A2, A4, M1, M2, and M3 and the presence of a novel form designated GST "A5." GSTA2 consiste d of three forms that were differentially expressed between individuals in a manner consistent with allelic polymorphism at the hGSTA2 locus. Expressi on, in terms of mu g 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 Al and M2. L ess consistently expressed were GSTs M1a, M1b, A4, and A5. Among these, GST M1 expression (excluding M1-null samples) varied 12-fold between samples, w hereas GST Al and A5 expression varied similar to 50-100-fold between sampl es, well beyond the range of other subunits, suggesting that their expressi on is highly inducible. Linear correlations (P < 0.001-0.003) existed betwe en levels of the most:consistently expressed GST, GSTP1, and total GSTs, GS TA2 and M3, and in GSTM1-positive samples, between GSTM1, M3, and P1. The c orrelation between GST subunits P1 and M3 was bimodal according to M1 genot ype, 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 o f regulation of expression of GSTs occurs in human pancreas, the variabilit y of phenotype is high and might obscure the effects of genetic polymorphis ms on individual cancer susceptibility. Interindividual variation of GST ex pression is, therefore, a factor that should be taken account of in epidemi ological studies.