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'-hexachlorobi phenyl, a ''phenobarbital-like'' inducer of hepatic cytochrome P450, o n the CYP2B1 and CYP2B2 enzymes in the phenotypically obese fa/fa Zuck er rat. The fa/fa Zucker rat demonstrated a markedly lower level of CY P2B1/2B2 enzyme induction, as indicated by reduced enzyme activity (te stosterone 16 beta-hydroxylation and pentoxyresorufin O-dealkylation), protein concentration (Western blot), and mRNA (slot blot) than the l ean Fa/? rodents after in vivo treatment with 2,2',4,4',5,5'-hexachlor obiphenyl. A primary hepatocyte cell culture system was used to contro l for possible differences in the disposition of 2,2',4,4',5,5' -hexac hlorobiphenyl and hormonal dissimilarity between obese and lean Zucker rats. In agreement with the in vivo study, hepatocytes from fa/fa Zuc ker rats treated with 2,2',4,4',5,5'-hexachlorobiphenyl exhibited a po or induction response based on measurement of CYP2B1/2B2 mRNA. These d ata are similar to those reported earlier that demonstrate resistance of the CYP2B1/2B2 genes to the inductive effects of phenobarbital in f a/fa Zucker rats. Apparently a genetic defect in obese Zucker rats imp airs the increase in CYP2B1/2B2 gene transcription after treatment wit h phenobarbital as well as 2,2'4,4'5,5 '-hexachlorobiphenyl. This stud y provides evidence that phenobarbital and ''phenobarbital-like'' indu cers share a common cellular element(s) in the induction process of th e CYP2B1/2B2 enzymes.-