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 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.
Zannikos
P N
PN
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington.
Bandyopadhyay
A M
AM
Robertson
L W
LW
Blouin
R A
RA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C025619:steroid 16-beta-hydroxylase; C014024:2,4,5,2',4',5'-hexachlorobiphenyl