EXPRESSION AND POLYMORPHISM OF GLUTATHIONE-S-TRANSFERASE IN HUMAN LUNGS - RISK-FACTORS IN SMOKING-RELATED LUNG-CANCER

The relationships between smoking and the expression of glutathione S- transferase (GST) isozymes GSTM1-1, GSTM3-3, GSTP1-1 and GSTA1-1/2-2 (GSTA1/2), or between smoking and activities of epoxide hydrolase (EH) and aryl hydrocarbon hydroxylase (AHH) were investigated in lung samp les from 27 patients with lung cancer and 11 control patients by immun oblot analysis and enzyme assays, Determination of genotypes in blood leucocyte DNA showed that possession of the mu-class GSTM1 gene was cl osely related to the expression of GSTM1-1 and GSTM3-3 enzymes in lung cytosol: patients with the GSTM1 null genotype had no detectable GSTM 1 protein and less GSTM3 protein than patients with the GSTM1 gene (P < 0.001), Absence of the GSTM1 gene did not affect the content of pi-c lass GSTP1-1 or alpha-class GSTA1/2, GST activity towards 1-chloro-2,4 -dinitrobenzene was lower (P < 0.01) in patients lacking the GSTM1 gen e than in those expressing GSTM1; in general, patients with a low GSTM 3-3, GSTP1-1 or GSTA1/2 content also had significantly less overall GS T activity. The pulmonary content of GSTP1-1 was greater in cancer tha n in non-cancer patients (P < 0.05), Smoking did not influence the lev els of GST isozymes or the EH activity, In contrast, the AHH activity was significantly (P < 0.01) increased by smoking. Neither AHH nor EH showed a correlation with GSTM1 polymorphism. Our data support the ide a that in smokers who lack the GSTM1 gene, activation of carcinogens i n tobacco smoke (e.g. benzo[a]pyrene) is increased, while the efficacy of detoxification is limited both qualitatively (absence of GSTM1-1 e nzyme and low expression of GSTM3-3 enzyme) and quantitatively (low ov erall GST activity), This imbalance iii the metabolism of carcinogens may explain the increased susceptibility to lung cancer reported in sm okers with the GSTM1 null genotype.