Inhibition of human cytochrome P450 3A4 activity by zinc(II) ion.
Effects of Zn2+ on the activity and conformation of cytochorome P450 3A4 (CYP3A4) were investigated. Zn2+ specifically inhibited the testosterone 6beta-hydroxylation activity of CYP3A4 with an IC50 value of 27 microM. Zn2+ inhibited the CO-binding spectra of CYP3A4 reduced by NADPH-cytochrome P450 reductase (CPR) and NADPH only in the presence of b5. Zn2+-induced conformational changes of CYP3A4 were monitored by CD and intrinsic fluorescence. Zn2+ showed no significant effects on the activity of CYP3A4 supported by tert-butyl hydroperoxide, an oxygen surrogate, and on the reduction of b5 by CPR and NADPH. These results suggest that the inhibitory effects of Zn2+ come from preventing the stimulation of b5 on CYP3A4 activity.
Kim
Joon-Sik
JS
AngioLab, Paichai University, Taejon 302-735, Republic of Korea.
Yun
Chul-Ho
CH
D002248:Carbon Monoxide / Q000378:metabolism; D002942:Circular Dichroism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013739:Testosterone / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D013739:Testosterone; D002248:Carbon Monoxide; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D020122:tert-Butylhydroperoxide; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009251:NADPH-Ferrihemoprotein Reductase; D015032:Zinc