Inhibition of cytochrome P450 2C9 activity in vitro by 5-hydroxytryptamine and adrenaline.
In the present study, the occurrence of a modulatory effect of 14 neurotransmitters, precursors and metabolites on the cytochrome P450 2C9 (CYP2C9) enzyme activity, as determined by diclofenac 4-hydroxylation, was studied in human liver microsomes. Two indoleamines, 5-hydroxytryptamine (5-HT) and adrenaline, showed a non-competitive-type inhibitory effect of approximately 90% of the diclofenac 4-hydroxylase activity, with Ki values of 63.5 (0.7 and 156 (89.3 microM, respectively. The rest of substances analysed were weak inhibitors or had no inhibitory effect. CYP2C subfamily is present in human brain, although CYP2C9 isozyme has not yet been identified in this tissue, and CYP2C9 is involved in the metabolism of psychoactive drugs. Therefore, the fact that endogenous compounds could modulate the CYP2C9 activity, suggests that an hypothetical local activity of brain CYP2C9 might be susceptible to regulatory mechanisms. The possible clinical implications of this modulation are discussed.
Gervasini
G
G
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
Martínez
C
C
Agúndez
J A
JA
García-Gamito
F J
FJ
Benítez
J
J
D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D012701:Serotonin / Q000494:pharmacology*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013426:Sulfaphenazole / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D013426:Sulfaphenazole; D004008:Diclofenac; D012701:Serotonin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C108036:4'-hydroxydiclofenac; D004837:Epinephrine