Inhibition of apoptosis in rat hepatocytes treated with 'non-dioxin-like' polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are among the most prominent persistent en vironmental pollutants exhibiting neurotoxic, teratogenic and tumour-promot ing effects in experimental animals. `Dioxin-like' properties have been ass igned to a number of PCBs whereas other PCBs have been classified as 'non-d ioxin-like'. Many of the latter congeners are inducers of cytochrome P450 ( CYP) 2B1 and 2B2 similar to the liver tumour promoter phenobarbital. In con trast, 'dioxin-like' PCBs induce CYP1A isozymes, and other congeners have b een classified as 'mixed-type' inducers. Inhibition of apoptosis of pre-neo plastic hepatocytes is thought to play a central role in tumour promotion i n rat liver. We have used the inhibition of UV-induced apoptosis in rat hep atocytes in primary culture as an in vitro model for mechanistic studies on the inhibition of apoptosis. It could be shown that phenobarbital, and the 'non-dioxin-like' PCBs 28, 101 and 187 completely inhibit UV-induced apopt osis. The concentration-response curves and EC50 values for this effect, ho wever, were different from those of induction of CYP2B1/2B2-catalysed 7-pen toxyresorufine O-dealkylase or CYP1A-catalysed 7-ethoxyresorufine O-deethyl ase activities. The PCBs and phenobarbital did not affect the spontaneous i ncidence of apoptotic nuclei. In conclusion, 'non-dioxin-like' PCBs are lik ely to promote liver carcinogenesis via the suppression of apoptosis. The s ignaling events in rat hepatocytes leading to induction of 2B1/2B2 activity by the compounds investigated are assumed to differ from those leading to inhibition of apoptosis.