EXPRESSION OF THE CYP3A AND CYP2C11 ENZYMES IN A NUTRITIONALLY OBESE RODENT MODEL - RESPONSE TO PHENOBARBITAL TREATMENT

In this study, the overfed rat was employed as a model for examining t he influence of obesity on the regulation of hepatic cytochromes P450 3A and 2C11 (CYP3A and CYP2C11, respectively). These proteins represen t the predominant constitutive hepatic P450 enzymes of male rats. Spra gue-Dawley rats were chronically fed a standard pelleted diet or an en ergy-dense diet which typically results in significant increases in bo dy weight, serum triglyceride levels and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P450 content. Similar baseline activities of CYP3A (testosterone GP-hydroxylation), comparative CYP3A protein levels (Western blot) and steady-state CYP3 A mRNA (slot blot), were found in rats fed either diet. Likewise, obes ity did not appear to influence CYP2C11 at the enzyme activity (testos terone Pa-hydroxylation) or mRNA levels. Half of the animals in each g roup received 20 mg phenobarbital (intraperitoneal injection) per anim al every 12 hours for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital tre atment increased the concentrations of total cytochrome P450 in both l ean and obese rats to the same extent. CYP3A activity, protein and mRN A levels were induced to a similar magnitude in rats fed either diet. Furthermore, obesity did not influence CYP2C11 activity or mRNA levels following administration of phenobarbital. A lack of an effect of obe sity and the altered lipid environment on the regulation of CYP3A and CYP2C11 is in contrast to other enzymes studied previously. It is appa rent that the consequences of obesity on hepatic cytochrome P450 may b e enzyme-specific.