Structure and physiological function of human and rat glutathione S-transferase

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Multiple molecular forms of hepatic glutathione S-transferase (GST) were purified from three animal species. Among the 5 human GSTs (I-V) separated on chromatofocusing, type II was the hybrid of I and IV and type V was identical with the placental GST- <pi> . Of the four subunits (Ya, Yb, Yc and Yp) consisting the seven dimeric rat GSTs ( <L_2> , BL, <B_2> , <A_2> , AC, <C_2> , <P_2> ), Yb was separated into two species (Yb, Yb') which, together with Yp, were further composed of two microspecies differing 0.3 unit in their isoelectric points on two-dimensional gel electrophoresis. Only three major forms (I-III) were present in male mouse liver. Despite that human (V), rat ( <P_2> , GST-P) and mouse (II) were closely related in substrate specificities, N-terminal amino acid sequences and immunological crossreactivities, the former two existed in very low amounts in respective livers, whereas mouse II was the predominant in the male liver, where the expression was, strikingly, controlled … More by testosterone. Following our finding that the polypeptide which was most markedly increased in preneoplastic rat livers induced by administration of diethylnitrosamine and 2-fluorenylacetamide was identical with the subunit of placental GST-P together with the immunohistochemical demonstration of its specific localization in the enzyme-altered foci, we have established the purification method from the preneoplastic tissue. Foci were also inducible in rat livers by other carcinogens but not by noncarcinogens with minor exceptions. Single and multiple cells positive for GST-P were detectable in rat livers several days after administration of diethylnitrosamine, suggesting that the microscopic cells are possible precursors of the foci. GST-P had an additional peroxidase activity to detoxicate organic hydroperoxides. furthermore, it showed enantioselective GSH-conjugating activity for 9,10-dihydroxybenzo a pyrene 7,8-oxide. GST-P could be an excellent marker enzyme in the analysis of carcinogenic processes due to its specificity and the extraordinary high immunohistochemical sensitivity for the preneoplastic cells. Less