Cellular biochemical determinants modulating the metabolism of estrone 3,4-quinone.
The metabolism of the o-quinone derivative of estrone, 3,4-estrone quinone (3,4-EQ), has been investigated in human breast cancer cells. Unlike the p-quinone, diethylstilbestrol 4',4"-quinone, 3,4-EQ was not a substrate for the two-electron reduction catalyzed by the putative detoxifying enzyme, NAD(P)H:quinone reductase ( DT diaphorase; DT D). Accordingly, the DNA damage induced by 3,4-EQ in human MCF-7 cells was not affected by an inhibitor of DT D. Although 3,4-EQ was not an apparent substrate for the two-electron reduction catalyzed by DT D, this o-quinone was a substrate for the one-electron reduction catalyzed by cytochrome P450 reductase. The one-electron reduction of 3,4-EQ catalyzed by cytochrome P450 reductase occurred in the face of a significant and 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 metabolism was evaluated; surprisingly, SOD inhibited the hydrogen peroxide produced by this o-quinone. Possible reasons for the SOD-mediated inhibition of redox cycling of 3,4-EQ are discussed. In summary, important differences in the metabolism of 3,4-EQ vis-a-vis o- and p- quinones have been observed, and the implications of these differences are discussed.[1]References
- Cellular biochemical determinants modulating the metabolism of estrone 3,4-quinone. Nutter, L.M., Zhou, B., Sierra, E.E., Wu, Y.Y., Rummel, M.M., Gutierrez, P., Abul-Hajj, Y. Chem. Res. Toxicol. (1994) [Pubmed]
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