Regulation of the mouse liver cytochrome P450 2B subfamily by sex hormones and phenobarbital.
The sex-dependent expression and inducibility of the cytochrome P450 2B subfamily was studied in DBA/2 and Balb/c mice, and their F1 recombinants, at the mRNA, protein and activity levels. Analysis of poly(A)+ RNA with specific oligonucleotide probes directed to known mRNAs within the mouse 2B subfamily revealed that the levels of P450 2b-10 and 2b-9 mRNAs were co-regulated with two proteins (56 and 53 kDa) detected by a 2B-specific polyclonal antibody. Other mRNAs related to the 2B subfamily were barely or not at all detectable, and did not coincide with protein expression, suggesting that P450s 2b-9 and 2b-10 are the major 2B isoenzymes present in mouse liver. Specifically, castration of males increased the expression of 2b-9 and 2b-10 mRNAs and protein up to female levels, and testosterone administration to castrated mice reversed these changes. Ovariectomy of females appears to increase the expression of these P450s slightly. 2b-10, but not 2b-9, mRNA and protein were induced by phenobarbital. Based on immunoinhibition studies and the levels of these isoenzymes, P4502b-10 appears to be the major catalyst of 7-pentoxyresorufin O-dealkylation. Both P4502b-9 and P4502b-10 contribute up to 30% of the testosterone 16 alpha-hydroxylation, the balance being catalysed by P450s within the 2D subfamily. These experiments show that the female-predominant expression of the two mouse liver isoenzymes P4502b-9 and P4502b-10 is dependent on sex hormones. The fact that P4502b-9 does not respond to phenobarbital, while P4502b-10 is regulated by both phenobarbital and sex hormones, demonstrates the complexity of P450 expression even within one subfamily.
Honkakoski
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P
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Kojo
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A
Lang
M A
MA
D000595:Amino Acid Sequence; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009919:Orchiectomy; D010052:Ovariectomy; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013739:Testosterone / Q000494:pharmacology
D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D013739:Testosterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D039181:Steroid 16-alpha-Hydroxylase; D010634:Phenobarbital