Expression of a male-specific cytochrome P450 isozyme (CYP2C11) in fa/fa Zucker rats: effect of phenobarbital treatment.
The present study determined the effect of genetic obesity and phenobarbital (PB) treatment on the expression and regulation of the hepatic cytochrome P450 enzyme (CYP2C11) in Fa/? and fa/fa Zucker rats. Hepatic CYP2C11 levels as determined by Western immunoblotting and associated enzymatic activity (testosterone oxidation at the 2 alpha position) were significantly lower in untreated fa/fa Zucker rats compared with that observed in Fa/? Zucker rats. There was no significant difference in the constitutive CYP2C11 steady-state mRNA level hybridizable to the cDNA (P450 16 alpha) or specific oligonucleotide probe (Northern and slot blot analyses) between fa/fa and Fa/? Zucker rats. The depressed constitutive CYP2C11 protein levels in fa/fa rats may be attributed to their low plasma testosterone and growth hormone levels; however, lack of differences in CYP2C11 steady-state mRNA suggest post-transcriptional regulatory mechanism(s). Treatment with PB further suppressed hepatic CYP2C11 protein levels and activities in both fa/fa and Fa/? Zucker rats in comparison with that seen in controls. The level of CYP2C11 steady-state mRNA was significantly higher after treatment with PB in Fa/? Zucker rats, while no change was observed in fa/fa animals. The mechanism by which PB treatment fails to increase CYP2C11 steady-state mRNA levels in the fa/fa Zucker rat is unknown; however, it may share a common molecular basis with the defect in nuclear transcription rate previously observed with CYP2B1/2B2.
Bandyopadhyay
A M
AM
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington 40536.
Chaudhary
I
I
Robertson
L W
LW
Gemzik
B
B
Parkinson
A
A
Blouin
R A
RA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004247:DNA; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006579:Heterozygote; D006720:Homozygote; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D008969:Molecular Sequence Data; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011924:Rats, Zucker; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D013739:Testosterone / Q000378:metabolism
D007527:Isoenzymes; D012333:RNA, Messenger; D013739:Testosterone; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D010634:Phenobarbital