FOCAL NUCLEAR HEPATOCYTE RESPONSE TO OXIDATIVE DAMAGE FOLLOWING LOW-DOSE THIOACETAMIDE INTOXICATION

Rats were treated with low doses of the hepatocarcinogen thioacetamide . Forty-eight hours following this treatment, microscopic foci of hepa tic injury were observed, which were surrounded by a peripheral rim of histologically normal hepatocytes. These peripheral hepatocytes gener ally contained enlarged nuclei, and showed nuclear staining for 4-hydr oxynonenal-protein adducts, indicative of nuclear oxidative damage. In these same hepatocytes, we also observed specific focal nuclear induc tion of mu-class glutathione-S-transferase and alcohol dehydrogenase I , two enzymes which are important in metabolism of 4-hydroxynonenal, O f particular interest was the concurrent nuclear induction of APE/ref- 1, a multifunctional DNA repair enzyme which can function as a redox f actor, and of the transcription factor Jun, whose DNA binding is facil itated by APE/ref-1. These results document an orchestrated focal nucl ear response to oxidative damage produced by thioacetamide administrat ion, and may relate to the permanent effects produced by this treatmen t.