Inhibition of human cytochrome P450 3A4 activity by zinc(II) ion

Abstract Effects of Zn 2+ on the activity and conformation of cytochorome P450 3A4 (CYP3A4) were investigated. Zn 2+ specifically inhibited the testosterone 6β-hydroxylation activity of CYP3A4 with an IC 50 value of 27 μM. Zn 2+ inhibited the CO-binding spectra of CYP3A4 reduced by NADPH-cytochrome P450 reductase (CPR) and NADPH only in the presence of b 5 . Zn 2+ -induced conformational changes of CYP3A4 were monitored by CD and intrinsic fluorescence. Zn 2+ showed no significant effects on the activity of CYP3A4 supported by tert -butyl hydroperoxide, an oxygen surrogate, and on the reduction of b 5 by CPR and NADPH. These results suggest that the inhibitory effects of Zn 2+ come from preventing the stimulation of b 5 on CYP3A4 activity.