OVER-EXPRESSION OF GLUTATHIONE-S-TRANSFERASE YP ISOZYME AND CONCOMITANT DOWN-REGULATION OF YA ISOZYME IN RENAL-CELL CARCINOMA OF RATS INDUCED BY FERRIC NITRILOTRIACETATE

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal prox imal tubular damage, a consequence of iron-catalysed Fenton-like react ions, that finally leads to a high incidence of renal cell carcinoma ( RCC) in rodents. Glutathione S-transferase (GST) is a family of enzyme s that play an important role in detoxification of hydrophobic and ele ctrophilic molecules, and has been associated with putative preneoplas tic foci of rat hepatocarcinogenesis and chemotherapy-resistance of hu man cancers. Our previous study revealed an induction of pi-class glut athione S-transferase (Yp) mRNA in the kidney 3 h after administration of Fe-NTA, In the present study, expression of GST isozymes were furt her investigated in the Fe-NTA-induced RCCs of rats which are characte rized by (I) high incidence of metastasis and invasion, (2) high incid ence of tumour-associated mortality, and (3) possible involvement of r eactive oxygen species in carcinogenesis. In the Fe-NTA-induced RCCs, the levels of a-class GST (Ya) mRNA and proteins were markedly decreas ed with no apparent change in the copy number of the gene, In contrast , GST-YI, mRNA and proteins were significantly increased in the RCCs w hile the total GST enzymatic activity was decreased. Immunohistochemic al analysis revealed intense staining of GST-Yp not only in the primar y RCCs and its metastatic sites, but also in their non-tumorous part o f proximal tubules. The contrastive expression of GST isozymes in this renal carcinogenesis model suggests an alteration of its transcriptio n mechanisms and warrants further investigation of this particular det oxifying enzyme from the viewpoint of reactive oxygen species-induced carcinogenesis.