MOLECULAR-ORIGIN OF CANCER - CATECHOL ESTROGEN-3,4-QUINONES AS ENDOGENOUS TUMOR INITIATORS

Cancer is a disease that begins with mutation of critical genes: oncog enes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon-DNA adducts gene rate oncogenic mutations found in mouse skin papillomas (Proc. Natl. A cad. Sci. USA 92:10422, 1995). These mutations arise by mis-replicatio n of unrepaired apurinic sites derived from the loss of depurinating a dducts. This relationship led us to postulate that oxidation of the ca rcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E-1) and estr adiol (E-2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in e lectrophilic intermediates that covalently bind to DNA to form depurin ating adducts. The resultant apurinic sites in critical genes can gene rate mutations that may initiate various human cancers. The noncarcino genic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA a dducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to f orm the depurinating adduct 4-OHE1(E-2)-1(alpha,beta)-N7Gua at 59-213 mu mol/mol DNA-phosphate whereas the level of stable adducts was 0.1 m u mol/mol DNA-phosphate. In female Sprague-Dawley rats treated by intr amammillary injection of E-2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 mu mol 4-OHE2-1(alpha,beta)-N7Gua/mol DNA-phosphate. When 4-OHE1(E-2) were activated by horseradish peroxida se, lactoperoxidase, or cytochrome P450, 87-440 mu mol of 4-OHE1(E-2)- 1(alpha,beta)-N7Gua was formed, After treatment with 4-OHE2, rat mamma ry tissue contained 1.4 mu mol of adduct/mol DNA-phosphate. In each ca se, the level of stable adducts was negligible. These results, complem ented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.