Equine Estrogens

Long-term estrogen replacement therapy of postmenopausal women is associated with a clear risk for endometrial cancer and a possible risk for mammary cancer [18,19]. The most widely prescribed estrogen replacement formulations

4-hydroxy-EQ 4-hydroxy-EQ quinone
Fig. 3. Pathways proposed for the metabolic activation of equine estrogens

in the USA are derived from the urine of pregnant mares (e.g., Premarin) and contain, in addition to E2 and E1, significant amounts of steroidal estrogens with an unsaturated B ring, i.e., equilin (EQ) and equilenin (EN). Both EQ and EN are carcinogenic in the Syrian hamster kidney model [20]. Studies on the metabolism and genotoxicity of EQ and EN have recently been summarized by Bolton et al. [21]. In analogy to E2 and E1 (see above), EQ and EN undergo metabolic hydroxylation at C-2 and C-4 to yield catechols (Fig. 3). Interestingly, increasing the number of double bonds in the B ring favors hydroxylation at C-4 over C-2. As discussed above for the 4-hydroxylated E1 and E2, this pathway may lead to carcinogenic metabolites. It has been observed that both 4-hy-droxy-EQ and 4-hydroxy-EN readily autoxidize to the respective ortho-quinones, and the quinone of 4-hydroxy-EQ isomerizes and autoxidizes to the quinone of 4-hydroxy-EN (Fig. 3). 4-Hydroxy-EN appears to undergo redox cycling and to generate ROS, as it causes DNA single strand breaks and oxidative damage to DNA bases in cell-free systems and also in human breast cancer cell lines [22, 23]. Reaction of 4-hydroxy-EN and also 4-hydroxy-EQ with DNA or deoxynucleosides in vitro gave rise to several different types of lesions including bulky stable adducts and apurinic sites [24]. More recently, 4-hydroxy-EN was shown to induce ROS, DNA single strands breaks, and oxidized DNA bases in two murine fibroblast cell lines to a much greater extent than 4-hydroxy-E1 [25]. The occurrence of DNA lesions in whole animals after administration of EQ and EN and the mutagenicity of these equine estrogens or their metabolites remain to be demonstrated.

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