title: Cyclosporine metabolism by rat liver microsomes. Evidence for involvement of enzyme(s) other than cytochromes P-450 3A.
abstract: Cyclosporine (CyA) metabolism was investigated in liver microsomes obtained from untreated male and female Sprague-Dawley rats, and rats pretreated with ethinyl estradiol (EE), dexamethasone (DX), and phenobarbital (PB). Total hepatic microsomal cytochrome P-450 content of DX- and PB-treated male and female rats was significantly higher than that of their respective control or EE-treated rats. However, CyA metabolism was significantly increased, by all drug pretreatments, both in male and female rats. EE increased (2-5 fold) the formation of AM9 (a hydroxylated metabolite) and AM1c (a cyclized-hydroxylated product) over the CyA concentration range tested (0.2-42 microM). DX and PB significantly increased (2- to 20-fold) all detected metabolites (AM1, another hydroxylated metabolite; AM9; AM4N, an N-demethylated product; and AM1c), especially at high substrate concentrations (above 1.25 microM). Immunoblot analyses revealed that the microsomal P-450 3A2 content was decreased in EE-treated male rats, but markedly induced in those treated with either DX or PB. P-450 3A1 was undetectable in untreated and EE-treated female rats, but greatly induced in DX-treated male and female rats. Examination of P-450 3A activity, using 6 beta-hydroxytestosterone formation as a probe, confirmed the immunoblot results. These studies suggest that enzyme(s), other than P-450s 3A1 and 3A2 also play a significant role in CyA metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacy, University of California, San Francisco 94143-0446.
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: M A
authors.initials: MA
authors.lastname: Correia
authors.forename: A E
authors.initials: AE
authors.lastname: Rettie
authors.forename: D C
authors.initials: DC
authors.lastname: Swinney
authors.forename: P E
authors.initials: PE
authors.lastname: Thomas
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016572:Cyclosporine / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D013739:Testosterone; D011374:Progesterone; D014859:Warfarin; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System