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 l iver and lung microsomal drug-metabolizing enzymes. In this study, in vivo i.p. administration of pyridine to rabbits caused a significant 3.4-fold in crease in kidney N-nitrosodimethylamine (NDMA) N-demethylase activity as co mpared to the activity in control rabbits. The same treatment also signific antly stimulated the activity of other cytochrome P4502E1-associated enzyme s. 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). SD S-PAGE of both kidney and liver microsomes of pyridine-treated rabbits show ed a protein band of enhanced intensity at 51,000 Mr migrating in the regio n of cytochrome P4502E1. p-Aminophenol, a 4-hydroxylation product of anilin e, has been shown to be nephrotoxic and NDMA, a procarcinogen, has been sho wn to be carcinogenic following bioactivation by NDMA N-demethylase in a nu mber of tissues including the kidney. Since pyridine was shown to be nephro toxic, it is expected that pyridine potentiates the toxic and/or carcinogen ic effects of aniline, p-nitrophenol and NDMA through induction of their me tabolism by the cytochrome P450-dependent drug-metabolizing enzymes.