Comparison of hepatic carcinogen initiation-promotion systems

A number of model systems have been developed to study the initiating and promoting phases of neoplastic development in rats liver. Four of these protocols use diethylnitrosamine (DEN) initiation, but employ different methods of promotion. The present studies were designed to evaluate these systems under standardized laboratory conditions to determine their relative ability to induce histochemically identifiable gamma-glutamyl transpeptidase positive (GGT+) foci. Studies were also performed to examine the effects of the four promoting regimens on liver-derived serum enzymes and hepatic drug metabolism. Under standardized laboratory conditions, including the use of a single rat strain, all four systems induced GGT+ foci following DEN initiation. Within the maximum time period evaluated (8 weeks) promotion with 2-acetylaminofluorene and partial hepatectomy resulted in the highest number of GGT+ foci/cm2. In addition, the hepatic mixed-function oxidase system was markedly affected by the promoting regimens. Cytochrome P-450 content was decreased (50% of control) by three of four systems. All four promotion regimens reduced benzphetamine-N-demethylase activity (20-50% of control). Ethoxycoumarin-O-deethylase activity (P-448 related) was not changed by the promotion regimens. Three of four regimens increased epoxide hydrolase activity (150-600% of control) and DT-diaphorase activity (150-200% of control). Combining DEN initiation and each of the four promotion protocols had little additional effect on hepatic drug metabolizing enzymes. It is concluded that the four systems evaluated are reproducible under standard conditions and that the promotion regimens employed cause striking alterations in hepatic microsomal drug metabolism that are largely independent of the presence or absence of focal GGT+ lesions.