REGULATION OF APOPTOSIS IN MOUSE HEPATOCYTES AND ALTERATION OF APOPTOSIS BY NONGENOTOXIC CARCINOGENS

Regulation of apoptosis is an important component of multistage hepato carcinogenesis. The objectives of the present study were to characteri ze apoptosis regulation in primary mouse hepatocytes and to determine whether nongenotoxic carcinogens alter apoptosis regulation. Bleomycin -induced apoptosis was accompanied by decreases in bcl-2 and bcl-xL an d increases in p53, bak, and bar protein levels. Transforming growth f actor (TGF)-beta-induced apoptosis was accompanied by decreased bcl-xL and increased bak. Bleomycin-induced apoptosis was partially dependen t on p53, whereas TGF-beta-induced apoptosis was independent of p53. P henobarbital inhibited both TGF-beta and bleomycin-induced apoptosis a nd the normal regulation of p53, bcl-2, and bar. Nafenopin inhibited a poptosis through a mechanism dependent on PPAR-alpha and inhibited the normal regulation of bcl-2 and bak, 2,3,7,8-Tetrachlorodibenzo-p-diox in did not alter apoptosis or its regulation. Apoptosis was increased in hepatocytes from bcl-2-null mice, which indicated that the bcl-2 fa mily contributes to hepatocyte apoptosis regulation. This study demons trated that apoptosis regulation in mouse hepatocytes involves distinc t pathways and that diverse nongenotoxic carcinogens differentially al ter molecular pathways that represent targets for hepatocarcinogenesis .