EFFECTS OF AN IMMUNOSUPPRESSIVE AGENT, TACROLIMUS (FK-506), ON THE ACTIVITIES OF CYTOCHROME P-450-LINKED MONOOXYGENASE SYSTEMS IN RAT-LIVERMICROSOMES

The effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-350-linked monooxygenase systems with resp ect to three cytochrome P-450 isozymes in rat Liver microsomes were in vestigated, FK-506 non-competitively inhibited the aniline p-hydroxyla se, p-nitroanisole O-demethylase and lidocaine N-deethylase activities of cytochrome P-450-linked monooxygenase systems, these activities be ing mainly catalyzed by cytochromes P-450 CYP2E1, CYP2C11 and CYP3A4, respectively, and the Ki values of the activities for FK-506 were dete rmined to be 605, 491 and 97 mu M, respectively. The inhibition of cyt ochrome P-450-linked monooxygenase systems by FK-506 seemed to involve the direct inhibition of cytochromes P-450 because the NADPH-cytochro me c reductase and NADPH-ferricyanide reductase activities of NADPH-cy tochrome 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 sp ectral change was induced on the addition of FK-506 to rat liver micro somes, and the Ks value was apparently 125 mu M. On the other hand, th e EPR spectra of cytochromes P-450 in rat liver microsomes were not af fected by 1 mM FK-506. These results suggest direct interaction betwee n FK-506 and cytochrome P-450 apoproteins, except for the heme iron re gions of cytochromes P-450, resulting in inhibition of the drug-metabo lism activities catalyzed by cytochromes P-450. (C) 1997 Elsevier Scie nce Ltd.