Document Detail

Effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems in rat liver microsomes.
MedLine Citation:
PMID:  9304807     Owner:  NLM     Status:  MEDLINE    
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.
K Izuishi; H Wakabayashi; T Ohnishi; H Maeta; T Maeba; Y Ichikawa
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The international journal of biochemistry & cell biology     Volume:  29     ISSN:  1357-2725     ISO Abbreviation:  Int. J. Biochem. Cell Biol.     Publication Date:  1997 Jun 
Date Detail:
Created Date:  1997-11-17     Completed Date:  1997-11-17     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9508482     Medline TA:  Int J Biochem Cell Biol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  921-8     Citation Subset:  IM    
Department of Surgery (1st Division), Kagawa Medical School, Japan.
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MeSH Terms
Aniline Hydroxylase / antagonists & inhibitors
Cytochrome P-450 Enzyme System / antagonists & inhibitors*
Enzyme Inhibitors / pharmacology*
Immunosuppressive Agents / pharmacology*
Microsomes, Liver / drug effects*,  enzymology
NADH, NADPH Oxidoreductases / drug effects
NADPH-Ferrihemoprotein Reductase / drug effects
Oxidoreductases / antagonists & inhibitors
Oxidoreductases, O-Demethylating / antagonists & inhibitors
Rats, Sprague-Dawley
Tacrolimus / pharmacology*
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Immunosuppressive Agents; 109581-93-3/Tacrolimus; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/4-nitroanisole O-demethylase; EC 1.-/Oxidoreductases; EC 1.-/Oxidoreductases, O-Demethylating; EC 1.-/lidocaine N-deethylase; EC 1.14.14.-/Aniline Hydroxylase; EC 1.6.-/NADH, NADPH Oxidoreductases; EC Reductase; EC 1.6.99.-/ferricyanide reductase

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