title: Distinct effects of phenobarbital and its N-methylated derivative on liver cytochrome P450 induction.
abstract: The relationship between barbiturate structures and their effects on induction of rat cytochrome P450 forms was studied in primary cultured hepatocytes. Treatment of hepatocytes cultured on matrigel with 1 mM barbital, N-methylbarbital, cyclobarbital, hexobarbital, phenobarbital (PB), or mephobarbital (N-methyl-PB) resulted in increased amounts of CYP2B1/2 and CYP2C6 forms. Microsomal CYP3A content was also enhanced by treatment with these barbiturates, except for barbital. Although no relationship was observed between the levels of CYP2B1/2 and CYP3A, ratios of CYP3A/CYP2B1 plus CYP2B2 contents were invariably higher with hepatocytes treated with N-methylated barbiturates than with the nonmethylated analogs. Consistent results were also observed in vivo in rats treated with PB and N-methyl-PB. These results indicate the difference in the structure requirement for induction of CYP2B and CYP3A. In addition, N-methyl-PB was found to suppress PB-mediated induction of CYP2B1. Hepatic levels of CYP2B1 mRNA and protein were increased by treatment with PB or N-methyl-PB alone, but decreased by cotreatment with 1 mM PB and N-methyl-PB. The suppression has been shown to occur at the transcriptional level of the CYP2B1 gene by using a chloramphenicol acetyltransferase reporter-CYP2B1 fused gene system.
authors.affiliation: Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Murayama
authors.forename: M
authors.initials: M
authors.lastname: Shimada
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: K
authors.initials: K
authors.lastname: Sogawa
authors.forename: K
authors.initials: K
authors.lastname: Nakayama
authors.forename: Y
authors.initials: Y
authors.lastname: Fujii-Kuriyama
authors.forename: R
authors.initials: R
authors.lastname: Kato
mesh_terms: D000818:Animals; D001483:Base Sequence; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects*; D008618:Mephobarbital / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010634:Phenobarbital / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism
chemical_list: D013739:Testosterone; D008618:Mephobarbital; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D010634:Phenobarbital