Stimulation of aniline, p-nitrophenol and N-nitrosodimethylamine metabolism in kidney by pyridine pretreatment of rabbits.
Pyridine has been shown to cause liver and kidney damage in animals and in humans. In a previous study we examined the effects of pyridine on rabbit liver and lung microsomal drug-metabolizing enzymes. In this study, in vivo i.p. administration of pyridine to rabbits caused a significant 3.4-fold increase in kidney N-nitrosodimethylamine (NDMA) N-demethylase activity as compared to the activity in control rabbits. The same treatment also significantly stimulated the activity of other cytochrome P4502E1-associated enzymes. The activities of p-nitrophenol hydroxylase and aniline 4-hydroxylase in kidney microsomes were increased 4.9-and 4.5-fold, respectively. Pyridine treatment increased the P450 content of the kidney 1.6-fold (P<0.05). SDS-PAGE of both kidney and liver microsomes of pyridine-treated rabbits showed a protein band of enhanced intensity at 51,000 Mr migrating in the region of cytochrome P4502E1. p-Aminophenol, a 4-hydroxylation product of aniline, has been shown to be nephrotoxic and NDMA, a procarcinogen, has been shown to be carcinogenic following bioactivation by NDMA N-demethylase in a number of tissues including the kidney. Since pyridine was shown to be nephrotoxic, it is expected that pyridine potentiates the toxic and/or carcinogenic effects of aniline, p-nitrophenol and NDMA through induction of their metabolism by the cytochrome P450-dependent drug-metabolizing enzymes.
Arinç
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Department of Biological Sciences, Middle East Technical University, Ankara, Turkey. earinc@metu.edu.tr
Adali
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Gençler-Ozkan
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D000814:Aniline Compounds / Q000378:metabolism*; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D013268:Stimulation, Chemical
D000814:Aniline Compounds; D009596:Nitrophenols; D009603:Nitroso Compounds; D011725:Pyridines; C008651:4-nitrosodimethylaniline; D019392:Cytochrome P-450 CYP2E1; D000815:Aniline Hydroxylase; D010089:Oxidoreductases, N-Demethylating; C023666:pyridine; C024836:4-nitrophenol