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 6 beta-hydroxylation activity of CYP3A4 with an IC50 value of 27 mu M. Zn2+ inhibited the CO-binding spectra of CYP3A4 reduced by NADPH-cytochrome P450 reductase (CPR) and NADPH only in the presenceof b(5).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 b(5) by CPR and NADPH. These results suggest that the inhibitory effects of Zn2+ come from preventing the stimulation of b(5) on CYP3A4 activity. (c) 2004 Elsevier Ireland Ltd. All rights reserved.