Differential effect of Cu2+ and Zn2+ on the formation and further metabolism of catechol estrogen by rat liver microsomes.

The action of a number of different divalent metal ions on the rat liver microsomal release of 3H2O from estradiol and 2-hydroxyestradiol labeled with 3H at C-2 or C-4 was investigated. Cu2+ at low concentration (10 microM) produced a marked and specific inhibition of the 2-hydroxylation of estradiol with virtually no effect on the further oxidative activation of catechol estrogen. In contrast, Zn2+ inhibited the interaction of 2-hydroxyestradiol with microsomal protein as measured by the release of 3H from C-4 of the labeled steroids but did not influence 2-hydroxylation, except at high concentration. Other metal ions tested produced little or no change. Cu2+ inhibited the irreversible binding of estradiol to protein but activated this reaction with the catechol estrogen as substrate. The action of both Cu2+ and Zn2+ was reversed by glutathione. The differential effect of these metal ions on estrogen metabolism gives additional support for two different mechanisms in the cytochrome P-450-catalyzed formation of catechol estrogens and their further activation to form protein conjugates.