DEPRESSION OF HEPATIC CYTOCHROME-P450 MONOOXYGENASES AFTER CHRONIC ENVIRONMENTAL TOBACCO-SMOKE EXPOSURE OF YOUNG FERRETS

Six-week-old ferrets were exposed head-only to clean air or environmen tal tobacco smoke (ETS) for 2 h/day, 5 days a week for a total of 8 we eks, Exposure to ETS caused a significant reduction in the levels of h epatic microsomal cytochrome P450 and P450 reductase activity in both the male and female ferrets. The content of cytochrome b(5) and the ac tivity of its reductase were significantly reduced in the hepatic micr osomes of female ferrets. 7-Ethoxycoumarin O-deethylase activity and c ytochrome P450 (CYP) 1A protein were markedly decreased in the hepatic microsomes of both the male and female ferrets after ETS exposure. In accord with the downregulation of P450, total metabolites formed from benzo[a]pyrene were significantly reduced in the liver homogenates of ETS-exposed animals. Similarly, sum total of free +)-anti-benzo[a]pyr ene-7,8-dihydrodiol-10-epoxide, glutathione conjugates and DNA-bound m etabolites formed from precursor (-)-7R-trans-benzo[a]pyrene-7,8-dihyd rodiol showed marked reduction in both the male and female ferrets aft er ETS exposure in a dose-response manner. This is the first report sh owing downregulation of hepatic P450 and accompanying benzo[a]pyrene m etabolism after tobacco smoke exposure which apparently occurred after an initial upregulation of these parameters