Carcinogenesis, Vol. 22, No. 10, 1601-1605,
October 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
Inhibition of apoptosis in rat hepatocytes treated with `non-dioxin-like' polychlorinated biphenyls
Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany
Polychlorinated biphenyls (PCBs) are among the most prominent persistent environmental pollutants exhibiting neurotoxic, teratogenic and tumour-promoting effects in experimental animals. `Dioxin-like' properties have been assigned to a number of PCBs whereas other PCBs have been classified as `non-dioxin-like'. Many of the latter congeners are inducers of cytochrome P450 (CYP) 2B1 and 2B2 similar to the liver tumour promoter phenobarbital. In contrast, `dioxin-like' PCBs induce CYP1A isozymes, and other congeners have been classified as `mixed-type' inducers. Inhibition of apoptosis of pre-neoplastic hepatocytes is thought to play a central role in tumour promotion in rat liver. We have used the inhibition of UV-induced apoptosis in rat hepatocytes 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 apoptosis. The concentration–response curves and EC50 values for this effect, however, were different from those of induction of CYP2B1/2B2-catalysed 7-pentoxyresorufine O-dealkylase or CYP1A-catalysed 7-ethoxyresorufine O-deethylase activities. The PCBs and phenobarbital did not affect the spontaneous incidence of apoptotic nuclei. In conclusion, `non-dioxin-like' PCBs are likely to promote liver carcinogenesis via the suppression of apoptosis. The signaling 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.
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