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.
Nemoto
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Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Ishikawa
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T
D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001551:Benz(a)Anthracenes / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009702:Nucleoside Diphosphate Sugars / Q000037:antagonists & inhibitors*; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors*; D012313:RNA / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D014158:Transcription, Genetic / Q000187:drug effects
D001551:Benz(a)Anthracenes; D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D011064:Poly Adenosine Diphosphate Ribose; D000628:Aminophylline; D012313:RNA; C025160:3-aminobenzamide; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; C030935:benz(a)anthracene; D001189:Aryl Hydrocarbon Hydroxylases; C025159:3-methoxybenzamide