1. Cytochrome P450 2B enzyme induction defect after 2,2',4,4',5,5'-hexachlorobiphenyl treatment in the fa/fa Zucker rat.
- Author
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Zannikos PN, Bandyopadhyay AM, Robertson LW, and Blouin RA
- Subjects
- Animals, Base Sequence, Body Weight drug effects, Cells, Cultured, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Enzyme Induction drug effects, Liver cytology, Liver drug effects, Liver enzymology, Male, Molecular Sequence Data, Oligodeoxyribonucleotides, Organ Size drug effects, RNA, Messenger metabolism, Rats, Rats, Zucker, Steroid Hydroxylases genetics, Steroid Hydroxylases metabolism, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 Enzyme System biosynthesis, Polychlorinated Biphenyls pharmacology, Steroid Hydroxylases biosynthesis
- Abstract
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 16 beta-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.
- Published
- 1994