[Enzyme alterations during chemical hepatocarcinogenesis].

Biochemical phenotypes such as the forms of enzyme proteins alter during the promotion and progression stages in chemical hepatocarcinogenesis. Many enzymes or isoenzymes have been identified as markers of (pre) neoplastic hepatic tissues and used for analysis of the carcinogenic process. The levels of hepatic isoenzymes decrease and those of prototypic or fetal isozymes increase during the progression of hepatocarcinogenesis. Some drug-metabolizing enzymes are also very variable at the promotion stage in rat chemical carcinogenesis; Phase I enzymes such as cytochrome P-450 decrease and Phase II (iso)-enzymes such as UDP-glucuronyl-transferase, glutathione S-transferase (GST) and gamma-glutamyl transpeptidase (gamma-GTP) increase. A new neutral GST form with pI 7.0 (GST-P) has been identified by us as one of the best markers for rat chemical hepatocarcinogenesis. GST-P is a homodimer consisting of a subunit (Mr 26,000, more accurately 23,307, and pI 6.7), the smallest among rat GST subunits, and differs immunochemically from any other GST form. It is present in very low levels in normal rat liver and is not inducible by most drugs including carcinogens without the appearance of preneoplastic hepatocyte nodules (HN) but it is increased by several ten-fold in HN-bearing liver and hepatomas induced by different carcinogens. Immunohistochemically, it is localized in HN and very early and small GST-positive foci are detectable using anti-GST-P antibody. (Pre) neoplastic hepatic lesions induced by nongenotoxic carcinogens such as hypolipidemic peroxisome-proliferating agents do not express GST-P as well as gamma-GTP.