Elevation of polycyclic aromatic hydrocarbon-inducible aryl hydrocarbon hydroxylase activity in rat hepatocytes in primary culture by inhibitors of poly(ADP-ribose) polymerase.

Induction of aryl hydrocarbon hydroxylase (AHH) activity was studied in primary cultures of rat hepatocytes. AHH activity was induced by treatment with benz[a]anthracene and combined treatment with cycloheximide for an initial short period during the induction enhanced benz[a]anthracene-inducible AHH activity. The enhancement was correlated to amounts of cytochrome P-450 RNA, indicating that cycloheximide treatment increased transcription of benz[a]anthracene-inducible cytochrome P-450 gene species. 3-Methoxybenzamide and 3-aminobenzamide, known to be physiologically specific inhibitors for poly(ADP-ribose) polymerase, but not the structurally related non-inhibitor, 3-aminobenzoic acid, also increased benz[a]anthracene-induced AHH activity. In addition, 3-methoxybenzamide was found to further increase the enhancing effects of cycloheximide on benz[a]anthracene induction of AHH. The effects of poly(ADP-ribose) polymerase inhibitors were not mediated by reduction of cyclic nucleotide phosphodiesterase activity. This was in clear contrast to the situation with the xanthine derivative, aminophylline, which also brought about a similar enhancement of AHH induction by benz[a]anthracene. The results suggest the participation of poly(ADP-ribose) in the regulation of expression of benz[a]anthracene-inducible cytochrome P-450 genes.