title: Rat cytochrome P450 2C11 in liver microsomes involved in oxidation of anesthetic agent propofol and deactivated by prior treatment with propofol.
abstract: Propofol (2,6-diisopropylphenol) is a widely-used anesthetic agent attributable to its rapid biotransformation. Liver microsomal cytochrome P450 (P450) isoforms involved in the biotransformation of propofol in rats and the effects of propofol in vivo on P450 levels in rats were investigated. Of six cDNA-expressed rat P450 isoforms tested, CYP2B1 and CYP2C11 had high catalytic activities from 5 microM and 20 microM propofol concentrations, respectively. Rates of propofol metabolism, at a substrate concentration of 20 microM based on the reported human blood concentration, were decreased by intraperitoneal treatment of propofol with male rats, in contrast to a strong induction by phenobarbital. Single intravenously administered propofol (10 mg/kg) caused the decrease of total P450 and CYP2C contents and activities of testosterone 16alpha-hydroxylation and propofol metabolism in liver microsomes from male rats. The suppressive effects were caused by administered propofol (10 mg/kg) twice every 4 h on CYP2B activities such as testosterone 16beta-hydroxylation or pentoxyresorufin O-depentylation, in addition to the strong suppression of CYP2C function by the single propofol treatment. These results suggest that CYP2C11, presumably deactivated by propofol, has an important role in propofol metabolism in rat liver microsomes. Repeated administration of propofol could markedly decrease the biotransformation of propofol via P450 deactivation.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo, Japan. hyamazak@ac.shoyaku.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Masaki
authors.initials: M
authors.lastname: Minoshima
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
mesh_terms: D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D002384:Catalysis; D000072467:Cytochrome P450 Family 2; D004789:Enzyme Activation; D004790:Enzyme Induction; D005260:Female; D008297:Male; D050216:Metabolic Detoxication, Phase I; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D015742:Propofol / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D018686:Anesthetics, Intravenous; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D015742:Propofol