Studies on the interaction of furan with hepatic cytochrome P‐450

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Abstract
In vitro incubation of rat liver micro‐somes with [14C]‐furan in the presence of NADPH resulted in the covalent incorporation of furan‐derived radioactivity in microsomal protein. Compared to microsomes from untreated rats a two‐ to threefold increase in binding was observed with microsomes from phenobarbital‐treated rats and a four‐ to five‐fold increase was observed with microsomes from rats pretreated with imidazole or pyrazole. Covalent binding was reduced with microsomes from rats pretreated with β‐naphthoflavone. Chemicals containing an amine group (semicarbazide), those in which the amine group is blocked but have a free thiol group (N‐acetylcysteine), and those which have both an amine and a thiol group (glutathione) effectively blocked binding of [14C]‐furan to microsomal protein. A decrease in cytochrome P‐450 (P‐450) content and decreases in the activities of P‐450‐dependent aniline hydroxylase, 7‐ethoxycoumarin‐O‐deethylase (BCD), and 7‐ethoxyresorufin‐O‐deethylase (ERD) was observed 24 hours after a single oral administration of 8 or 25 mg/kg of furan, suggesting that the reactive intermediate formed during P‐450 catalyzed metabolism could be binding with nucleophilic groups within the P‐450. In vitro studies indicated a significant decrease in the activity of aniline hydroxylase in pyrazole microsomes and BCD in phenobarbital microsomes without any significant change in the CO‐binding spectrum of P‐450 or in the total microsomal heme content, suggesting that furan inhibits the P‐450s induced by PB and pyrazole. An almost equal distribution of furan‐derived radioactivity in the heme and protein fractions of the CO‐binding particles after In vitro treatment of microsomes with furan suggests binding of furan metabolites with heme and apoprotein of P‐450, and, probably, due to this interaction, furan is acting as a suicide inhibitor of P‐450.