title: Rat cytochrome p450 1A and 3A enzymes involved in bioactivation of tegafur to 5-fluorouracil and autoinduced by tegafur in liver microsomes.
abstract: Tegafur, an anticancer prodrug, is reported to be bioactivated to 5-fluorouracil (5-FU) by cytochrome P450 (P450) enzymes. Liver microsomal P450 enzymes involved in the biotransformation of tegafur into 5-FU in rats and the effect of tegafur in vivo on P450 levels in rats were investigated. Of 12 cDNA-expressed rat P450 enzymes tested, CYP1A2, CYP3A1, and CYP2C11 had high 5-FU formation rates from 100 microM and 1.0 mM tegafur concentrations. The contributions of CYP1A, CYP2C, and CYP3A enzymes to 5-FU formation in male rat liver microsomes were supported by immunoinhibition studies. 5-FU formation from tegafur, at substrate concentrations of 100 microM and 1.0 mM, was increased by intraperitoneal treatment of tegafur (50 mg/kg for 5 days) as well as by beta-naphthoflavone, phenobarbital, and dexamethasone. Orally administered tegafur (100 mg/kg daily for 20 days) caused the induction of CYP2B (5-fold) and of CYP1A and CYP3A (approximately 2-fold) and of 5-FU formation (approximately 2-fold) in rat liver microsomes. These results suggest that CYP1A and CYP3A enzymes, autoinduced by tegafur, have important roles in 5-FU formation from tegafur in rat liver microsomes. Coadministration of tegafur and P450-inducing drugs could markedly enhance the biotransformation of tegafur into 5-FU via P450 induction.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamazaki
authors.forename: T
authors.initials: T
authors.lastname: Komatsu
authors.forename: K
authors.initials: K
authors.lastname: Takemoto
authors.forename: N
authors.initials: N
authors.lastname: Shimada
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
authors.forename: T
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D005641:Tegafur / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D011355:Prodrugs; D005641:Tegafur; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D005472:Fluorouracil