title: Comparative effects of topically applied nitrated arenes and their nonnitrated parent arenes on cutaneous and hepatic drug and carcinogen metabolism in neonatal rats.
abstract: The effect of a single topical application of several nitroarenes (1-nitropyrene, nitropyrenes mixture, nitrobenzo(ghi)perylene mixture, 3-nitrofluoranthene, nitrofluoranthene mixture, and nitroperylene mixture) and their corresponding parent arenes to neonatal rats on hepatic and cutaneous drug and carcinogen metabolism was studied. Topical application of each nitroarene (10 mg/kg) resulted in significant induction of aryl hydrocarbon hydroxylase (AHH), 7-ethoxyresorufin O-deethylase (ERD), and 7-ethoxycoumarin O-deethylase (ECD) activities in both skin (1.5- to 14.6-fold) and liver (1.3- to 41.9-fold). The induction of these enzymes by each of the nitroarenes was significant when compared to control or to their corresponding parent arenes. Among the nitroarenes studied, 1-nitropyrene was the least effective in inducing enzyme activities. The inducibility in both skin and liver by different nitroarenes tested was in the following order: nitrofluoranthenes mixture greater than 3-nitrofluoranthene greater than nitroperylenes mixture greater than nitrobenzo(ghi)perylenes mixture greater than nitropyrenes mixture greater than 1-nitropyrene. The nitrofluoranthenes mixture and the nitroperylenes mixture were almost as effective as 3-methylcholanthrene (3-MC). Parent arenes were either ineffective or significantly less effective than nitrated arenes in inducing hepatic and/or cutaneous monooxygenase activities. Hepatic and/or cutaneous benzphetamine N-demethylase (BPD), NADPH cytochrome c reductase, NADH ferricyanide reductase activities, and the levels of cytochrome P-450 and cytochrome b5, remained unchanged following treatment with either topically applied nitroarenes or arenes. However, a shift of approximately 1 nm to the blue region in the absorption maximum of hepatic cytochrome P-450 was observed in animals treated with nitroarenes. This shift was not evident in the case of 1-nitropyrene. Analysis of benzo(a)pyrene metabolites by high-pressure liquid chromatography revealed a significant enhancement in the production of metabolites by nitroarene-treated rat skin and liver microsomes. Our studies suggest that nitroarenes are inducers of hepatic and cutaneous monooxygenases in neonatal rats after topical administration and that they resemble the 3-MC type of inducers in this regard.
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase; D000287:Administration, Topical; D000818:Animals; D000831:Animals, Newborn; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D019363:Cytochrome P-450 CYP1A1; D004790:Enzyme Induction; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009574:Nitro Compounds / Q000633:toxicity*; D010088:Oxidoreductases / Q000096:biosynthesis*; D010105:Oxygenases / Q000096:biosynthesis*; D011083:Polycyclic Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012867:Skin / Q000187:drug effects* / Q000201:enzymology
chemical_list: D009574:Nitro Compounds; D011083:Polycyclic Compounds; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1