Inhibition of apoptosis in rat hepatocytes treated with 'non-dioxin-like' polychlorinated biphenyls.
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 EC(50) 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.
Bohnenberger
S
S
Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
Wagner
B
B
Schmitz
H J
HJ
Schrenk
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002478:Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects; D066298:In Vitro Techniques; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014466:Ultraviolet Rays
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D010634:Phenobarbital