Polycyclic aromatic hydrocarbons cause hepatic porphyria in iron-loaded C57BL/10 mice: comparison of uroporphyrinogen decarboxylase inhibition with induction of alkoxyphenoxazone dealkylations.
Multiple doses of beta-naphthoflavone to iron-loaded C57BL/10ScSn mice for 6 weeks caused inhibition of hepatic uroporphyrinogen decarboxylase and a porphyria indistinguishable from that previously only reported for polyhalogenated aromatic chemicals. beta-Naphthoflavone and other polycyclic aromatic hydrocarbon inducers of cytochrome P1-450-mediated ethoxyphenoxazone deethylation (ethoxyresorufin deethylase), benzo[a]pyrene, benz[a]anthracene, dibenz[ah]anthracene, 3-methylcholanthrene and alpha-naphthoflavone, also gave porphyria when fed. Isosafrole was inactive but by both methods phenobarbital produced a small but significant inhibition of the decarboxylase. The results demonstrate a toxic action of polycyclic aromatic hydrocarbons which probably does not involve reactive metabolites.
D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000633:toxicity; D001571:Benzoflavones / Q000633:toxicity; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D056486:Chemical and Drug Induced Liver Injury; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D007501:Iron / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000633:toxicity*; D011164:Porphyrias / Q000139:chemically induced*; D012451:Safrole / Q000494:pharmacology; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors*; D019324:beta-Naphthoflavone
D001551:Benz(a)Anthracenes; D001571:Benzoflavones; D011083:Polycyclic Compounds; D001564:Benzo(a)pyrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene; D007501:Iron; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase; D012451:Safrole; C015959:isosafrole; D010634:Phenobarbital