Dietary-induced obesity, hepatic cytochrome P450 and lidocaine metabolism: Comparative effects of high-fat diets in mice and rats and reversibility of effects with normalization of diet.

The effects of a high-fat diet on mRNA and protein of cytochrome P450 (CYP) enzymes in rats and mice, and its impact on lidocaine deethylation to its main active metabolite, monoethylglycinexylidide (MEGX) in rats were investigated. The effect of a change in diet from high-fat to standard diet was also evaluated. Plasma biochemistry, mRNA, protein expression for selected CYP and the activity of lidocaine deethylation was determined. The high-fat diet curtailed the activity and the expression the majority of CYPs (CYP1A2, CYP3A1, CYP2C11, CYP2C12 and CYP2D1), mRNA levels (Cyp1a2, Cyp3a2) and MEGX maximal formation rate (Vmax). Mice showed complimentary results in their protein expressions of cyp3a and 1a2. Switching the diet back to standard chow in rats for 4 wk reverted the expression levels of mRNA and protein back to normal levels as well as the maximum formation rates of MEGX. Female and male rodents showed similar patterns in CYP expression and lidocaine metabolism in response to the diets, although MEGX formation was faster in male rats. In conclusion, diet induced obesity caused general decreases in CYP isoforms in rat, but also in mice. The effects were shown to be reversible in rats by normalizing the diet.