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.