title: Effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems in rat liver microsomes.
abstract: The effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems with respect to three cytochrome P-450 isozymes in rat liver microsomes were investigated. FK-506 non-competitively inhibited the aniline p-hydroxylase, p-nitroanisole O-demethylase and lidocaine N-deethylase activities of cytochrome P-450-linked monooxygenase systems, these activities being mainly catalyzed by cytochromes P-450 CYP2E1, CYP2C11 and CYP3A4, respectively, and the Ki values of the activities for FK-506 were determined to be 605, 491 and 97 microM, respectively. The inhibition of cytochrome P-450-linked monooxygenase systems by FK-506 seemed to involve the direct inhibition of cytochromes P-450 because the NADPH-cytochrome c reductase and NADPH-ferricyanide reductase activities of NADPH-cytochrome P-450 reductase were not affected by the presence of 1 mM FK-506 at all. A spectrophotometric study showed that a reverse type I spectral change was induced on the addition of FK-506 to rat liver microsomes, and the Ks value was apparently 125 microM. On the other hand, the EPR spectra of cytochromes P-450 in rat liver microsomes were not affected by 1 mM FK-506. These results suggest direct interaction between FK-506 and cytochrome P-450 apoproteins, except for the heme iron regions of cytochromes P-450, resulting in inhibition of the drug-metabolism activities catalyzed by cytochromes P-450.
authors.affiliation: Department of Surgery (1st Division), Kagawa Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Izuishi
authors.forename: H
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: T
authors.initials: T
authors.lastname: Ohnishi
authors.forename: H
authors.initials: H
authors.lastname: Maeta
authors.forename: T
authors.initials: T
authors.lastname: Maeba
authors.forename: Y
authors.initials: Y
authors.lastname: Ichikawa
mesh_terms: D000815:Aniline Hydroxylase / Q000037:antagonists & inhibitors; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010090:Oxidoreductases, O-Demethylating / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C026048:4-nitroanisole O-demethylase; D010088:Oxidoreductases; D010090:Oxidoreductases, O-Demethylating; C108759:lidocaine N-deethylase; D000815:Aniline Hydroxylase; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; C014227:ferricyanide reductase; D016559:Tacrolimus