Effect of nutritional obesity on the induction of CYP2B enzymes following phenobarbital treatment

Human obesity is associated with a number of pathophysiologic processes, such as fatty infiltration and fibrosis of the liver. Although obesity has been shown to alter the metabolism of various xenobiotics, its effect on hepatic cytochromes P-450 is not known. In this study, the overfed rat was used as a model for examining the influence of obesity on the expression and regulation of hepatic cytochrome P-450 2B1/2B2. Sprague-Dawley rats were fed either a standard diet or an energy-dense diet for 32 weeks. The energy- dense diet resulted in a significant increase in body weight, serum triglyceride levels, and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P-450 content. Similar baseline activities of CYP2B1/2B2 (16β-testosterone hydroxylase and pentoxyresorufin O-dealkylation)-comparative protein levels of CYP2B1/2B2 (Western blot), and mRNA (slot blot)-were found in rats fed either diet. Half of the animals in each group were given 20 mg phenobarbital (intraperitoneal injection)/animal every 12 hr for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of cytochrome P-450 in both groups to the same extent. However, greater CYP2B1/2B2 activity was found in control rats following phenobarbital administration, whereas the amount of protein and mRNA was similar in each treated group. In conclusion, obesity did not affect the regulation of CYP2B1/2B2 enzymes. However, changes in the lipid environment associated with obesity may have affected the activity of these proteins.