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 environmental tobacco smoke (ETS) for 2 h/day, 5 days a week for a total of 8 weeks. Exposure to ETS caused a significant reduction in the levels of hepatic microsomal cytochrome P450 and P450 reductase activity in both the male and female ferrets. The content of cytochrome b5 and the activity of its reductase were significantly reduced in the hepatic microsomes of female ferrets. 7-Ethoxycoumarin O-deethylase activity and cytochrome 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]pyrene-7,8-dihydrodiol-9,10-epoxide, glutathione conjugates and DNA-bound metabolites formed from precursor (-)-7R-trans-benzo[a]pyrene-7,8-dihydrodiol showed marked reduction in both the male and female ferrets after ETS exposure in a dose-response manner. This is the first report showing downregulation of hepatic P450 and accompanying benzo[a]pyrene metabolism after tobacco smoke exposure which apparently occurred after an initial upregulation of these parameters (Rasmussen et al. (1994) FASEB J. 8, A122).
Sindhu
R K
RK
Department of Pathology, College of Medicine, University of California at Irvine 92717, USA.
Rasmussen
R E
RE
Yamamoto
R
R
Fujita
I
I
Kikkawa
Y
Y
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity; D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004781:Environmental Exposure; D005260:Female; D005289:Ferrets; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D011247:Pregnancy; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes; D014028:Tobacco Smoke Pollution; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D009251:NADPH-Ferrihemoprotein Reductase