CELLULAR BIOCHEMICAL DETERMINANTS MODULATING THE METABOLISM OF ESTRONE 3,4-QUINONE

The metabolism of the o-quinone derivative of estrone, 3,4-estrone qui none (3,4-EQ), has been investigated in human breast cancer cells. Unl ike the p-quinone, diethylstilbestrol 4',4''-quinone, 3,4-EQ was not a substrate for the two-electron reduction catalyzed by the putative de toxifying enzyme, NAD(P)H:quinone reductase (DT diaphorase; DT D). Acc ordingly, the DNA damage induced by 3,4-EQ in human MCF-7 cells was no t affected by an inhibitor of DT D. Although 3,4-EQ was not an apparen t substrate for the two-electron reduction catalyzed by DT D, this o-q uinone was a substrate for the one-electron reduction catalyzed by cyt ochrome P450 reductase. The one-electron reduction of 3,4-EQ catalyzed by cytochrome P450 reductase occurred in the face of a significant an d potentially physiologically relevant spontaneous reduction of 3,4-EQ by NADPH. The impact of purified superoxide dismutase (SOD) upon the production of hydrogen peroxide produced as a consequence of 3,4-EQ me tabolism was evaluated; surprisingly, SOD inhibited the hydrogen perox ide produced by this o-quinone. Possible reasons for the SOD-mediated inhibition of redox cycling of 3,4-EQ are discussed. In summary, impor tant differences in the metabolism of 3,4-EQ vis-a-vis o- and p- quino nes have been observed, and the implications of these differences are discussed.