Cytochrome P450 2B enzyme induction defect after 2,2',4,4',5,5'- hexachlorobiphenyl treatment in the fa/fa Zucker rat

The present study describes the effects of 2,2',4,4',5,5'- hexachlorobiphenyl, a 'phenobarbital-like' inducer of hepatic cytochrome P450, on the CYP2B1 and CYP2B2 enzymes in the phenotypically obese fa/fa Zucker rat. The fa/fa Zucker rat demonstrated a markedly lower level of CYP2B1/2B2 enzyme induction, as indicated by reduced enzyme activity (testosterone 16β-hydroxylation and pentoxyresorufin O-dealkylation), protein concentration (Western blot), and mRNA (slot blot) than the lean Fa/? rodents after in vivo treatment with 2,2',4,4',5,5'-hexachlorobiphenyl. A primary hepatocyte cell culture system was used to control for possible differences in the disposition of 2,2',4,4',5,5'-hexachlorobiphenyl and hormonal dissimilarity between obese and lean Zucker rats. In agreement with the in vivo study, hepatocytes from fa/fa Zucker rats treated with 2,2',4,4',5,5'-hexachlorobiphenyl exhibited a poor induction response based on measurement of CYP2B1/2B2 mRNA. These data are similar to those reported earlier that demonstrate resistance of the CYP2B1/2B2 genes to the inductive effects of phenobarbital in fa/fa Zucker rats. Apparently a genetic defect in obese Zucker rats impairs the increase in CYP2B1/2B2 gene transcription after treatment with phenobarbital as well as 2,2'4,4'5,5'-hexachlorobiphenyl. This study provides evidence that phenobarbital and 'phenobarbital-like' inducers share a common cellular element(s) in the induction process of the CYP2B1/2B2 enzymes.