The Oxidative Metabolism of the Aromatic A-Ring of Steroidal Estrogens

Abstract

The pathways of oxidative metabolism of the aromatic A-ring of steroidal estrogens such as estradiol involve initial hydroxylation reactions at C-2 and C-4. Estrogen 2-/4-hydroxylase activities, which catalyze the formation of the resulting catechol estrogen products, are found in microsomes from a variety of mammalian tissues. The relatively high rate of catechol estrogen formation in the liver has generally been regarded as a deactivating reaction because the catechol products were considered to be biologically inert. Recently, however, there has been a resurgence of interest in 2- and 4-hydroxy-estradiol due to their potential biological activities when they are formed within tissues, since these catechols are further metabolized extremely rapidly when they are administered to animals or humans. It has also become evident from differences between some of the biological activities of 2- and 4-hydroxy-estrogens that it is no longer appropriate to consider catechol estrogens as a single class of compounds.

There is relatively little information on the mechanism of microsomal estrogen 244-hydroxylase activities. In this paper it is proposed that the active intermediates are stabilized tautomers of dienol epoxides, related in structure to some of the intermediates known to be involved in the conversion of carcinogenic polycyclic aromatic hydrocarbons into their reactive ultimate carcinogens, the dihydrodiol epoxides. The chemistry of estrogen-derived dienol epoxides will be discussed and syntheses described. Biochemical results will be provided which implicate one of these dienol epoxide taumomers as an intermediate in the conversion of estradiol to 2-hydroxyestradiol.