Hepatic cytochrome P-450 and in vitro drug metabolism in an overfed rat model of obesity.
Liver microsomes from obese and control Sprague-Dawley rats were compared for cytochrome P-450 content and the ability to metabolize various prototype substrates. Over a 40-week period, the obesity-producing energy-dense diet increased average total body mass by 50%, liver mass by 32%, and body fat mass by 292%. Spectrally detectable cytochrome P-450 per mg protein increased by 36% in hepatic microsomes from obese rats. The livers from obese rats also contained more cytochrome P-450 (87%), while microsomal protein, NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase, and UDP-glucuronosyl transferase per organ rose slightly (12-40%) but not significantly. No change in the specific activities of these enzymes occurred. Young and adult rats were transferred from pellet diet to energy-dense diet for 3 weeks to examine the influence of diet vs. obesity. This short-term dietary change increased microsomal protein per g liver as well as cytochrome P-450 per liver, per g liver, and per mg protein. Adult animals increased in body weight by 24%, making them overweight and borderline obese. However, young animals showed no increase in body or liver weight, suggesting a direct effect of the energy-dense diet on liver P-450. Dietary obesity thus increased both the relative and total amounts of liver cytochrome P-450 in rats, but not the specific activities of other enzymes. These changes in cytochrome P-450 are consistent with the increased clearance seen for several oxidized drugs in obese humans and suggest that the obese overfed rat represents a useful animal model.
Matsumoto
R M
RM
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Jusko
W J
WJ
Corcoran
G B
GB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004195:Disease Models, Animal; D014453:Glucuronosyltransferase / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000032:analysis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D009596:Nitrophenols; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D009251:NADPH-Ferrihemoprotein Reductase; D014453:Glucuronosyltransferase; C024836:4-nitrophenol