Journal Article

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

Stefan Bohnenberger, Barbara Wagner, Hans-Joachim Schmitz and Dieter Schrenk

in Carcinogenesis

Volume 22, issue 10, pages 1601-1605
Published in print October 2001 | ISSN: 0143-3334
Published online October 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.10.1601
Inhibition of apoptosis in rat hepatocytes treated with `non-dioxin-like' polychlorinated biphenyls

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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.

Keywords: AhR, aryl hydrocarbon receptor; CYP, cytochrome P450; EROD, 7-ethoxyresorufin O-deethylase; DMEM, Dulbecco's modified Eagle's medium; PCBs, polychlorinated biphenyls; PROD, 7-pentoxyresorufin O-dealkylase; TCDD, 2,3,7,8-tetrachlordibenzo-p-dioxin; TEFs, toxicity equivalency factors.

Journal Article.  3649 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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