A Unified Mechanism in the Initiation of Cancer

Abstract

Estrogens are involved in the initiation of breast, prostate, and other kinds of human cancer. In this process, the endogenous estrogens, estrone and estradiol, are metabolized to 2-catechol estrogens (2-CE, major) and 4-CE (minor). If the 4-CEs are further oxidized to CE-3,4-quinones, they may react with DNA to form depurinating adducts at N-7 of guanine and N-3 of adenine, and generate apurinic sites. Similarly, the carcinogenic synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts with DNA to form analogous depurinating adducts. This could be the primary critical event leading to oncogenic mutations and then initiation of cancer. Evidence supporting this hypothesis has been obtained from the human breast and animal models susceptible to estrogen-induced tumors, including the Syrian golden hamster kidney, ACI rat mammary gland, and Noble rat prostate. The oxidation of phenols to catechols and then to quinones is not only a mechanism of tumor initiation for natural and synthetic estrogens, but also for the leukemogen benzene. In fact, catechol, one of the metabolites of benzene, when oxidized to its quinone, reacts with DNA to form N7guanine and N3adenine depurinating adducts. Thus, a unifying mechanism, namely formation of catechol quinones and reaction with DNA, could initiate not only cancer by oxidation of specific endogenous estrogen metabolites, but also leukemia by oxidation of benzene.