Estradiol and Estrone

The mammalian estrogens E2 and estrone (E1), which are interconvertible in the cell by the enzyme 17^-hydroxysteroid dehydrogenase, are human and animal carcinogens [1]. An established animal model is the male Syrian golden hamster, in which carcinogenic estrogens lead to a 100% incidence of kidney tumors. The observation that several potent steroidal estrogens, e.g., 17a-ethinyl-E2 and 2-fluoro-E2, are virtually noncarcinogenic for the hamster kidney [2] is not consistent with the paradigm that the stimulation of cell proliferation and the eventual accumulation of spontaneous mutations [3] is the cause of hormonal cancer. This was one of the reasons that prompted several laboratories to study other mechanisms, in particular the role of genotoxic metabolites. Several recent reviews have detailed the current state of knowledge in this field [4-10]. As depicted in Fig. 2, the major pathways in the oxidative metabolism of E2 and E1 comprise hydroxylation at C-2, C-4, and C-16. The catechol es-

Fig. 1. Chemical structures of various EACs o

2-Methoxy-E
Estradiol And Estrone
Fig. 2. Pathways proposed for the metabolic activation of E2 and El

trogens 2-hydroxy-E and 4-hydroxy E can either be conjugated, e.g., methylated, or further oxidized to semiquinones and quinones. The latter are reactive metabolites, covalently binding to glutathione (GSH), proteins, and DNA. Several adducts of the catechol estrogens with the DNA bases guanine and adenine have been identified in in vitro systems and, to a limited extent, also in vivo. The chemical structures of the adducts show that the 3,4-quinone reacts primarily through C-1 with the N7-position of guanine, whereas the 2,3-quinone tautomerizes to a quinone methide prior to reacting through C-6 with the exocyclic amino groups of adenine and guanine. The DNA adducts of the 2,3-quinone are chemically stable, in contrast to the adduct of the 3,4-quinone which is released from the DNA by spontaneous depurination.

It is believed that 4-hydroxylation is the critical pathway for the carcinogenicity of E2. The major reasons for this proposition are (i) 4-hydroxy-E2 but not 2-hydroxy-E2 is carcinogenic in the Syrian hamster kidney and also in another animal model, the neonatal CD-1 mouse uterus [11], (ii) 4-hydroxylation is predominating over 2-hydroxylation in the target tissues of E2 carcinogenicity, e.g., the hamster kidney and the human breast and uterus, due to the activity of the hydroxylating enzyme cytochrome P4501B1 (CYP1B1), and (iii) the depurinating DNA adducts are considered a more critical lesion for the initiation of cancer than the stable DNA adducts. Moreover, 4-hydroxy-E are less rapidly methylated by catechol-O-methyltransferase and thus less efficiently inactivated than their 2-hydroxylated isomers.

In addition to the formation of direct DNA adducts, catechol estrogens can give rise to indirect DNA adducts through redox cycling (Fig. 2). The generation of reactive oxygen species (ROS) can lead to oxidative DNA damage and lipid peroxidation, the latter generating reactive aldehydes which adduct DNA. Both types of ROS-mediated DNA modifications have been observed with E2 in target tissues in vivo.

Due to their potential to cause DNA damage, E2 and its catechol metabolites should give rise to gene mutations. Whereas earlier studies in standard mutagenicity test systems such as the Ames test gave negative results, a weak mutagenic response was found in more recent studies [12,13]. Interestingly, E2 mutagenicity was only observed at very low (10-100 pmol/l) and relatively high (0.1 -1 |imol/l) concentrations in one of the studies [12]. This may be due to the fact that catechol estrogens have both prooxidant and antioxidant properties, and the prooxidant effects may only be detected at certain concentrations [14]. Moreover, it may be assumed that E2 exhibits only very weak mutagenicity, which is not readily detected by the conventional short-term assays designed for strong mutagens.

The third major metabolite of E2, namely 16a-hydroxy-E1 (Fig. 2), has also been implicated in the mechanism of E2 carcinogenesis [15,16]. Due to the ability of the 17-keto group to form a Schiff base with amino groups and subsequently undergo an Amadori rearrangement with the 16a-hydroxyl group, this metabolite can form a stable protein or DNA adduct. It has been postulated that such a covalent modification of the estrogen receptor could lead to a persistent stimulation of cell proliferation in the mammary epithelium and thus favor the neoplastic progression of breast cancer.

To increase further the complexity of possible mechanisms of genetic toxicity of E2, numerical chromosomal aberrations (aneuploidy) have been observed with E2 and its catechol metabolites in vitro and in vivo. E2 and E1 caused aneuploidy and neoplastic transformation in cultured Syrian hamster embryo (SHE) fibroblasts even in the absence of detectable gene mutations [13]. The biochemical mechanisms underlying the aneuploidogenic effects are still poorly understood: E2 does not interfere with the mitotic spindle and may act through other components of the mitotic machinery, whereas the catechol metabolites, after oxidation to the quinones, bind covalently to critical sulfhydryl groups of tubulin and inhibit microtubule assembly and spindle formation [17].

In view of the plethora of effects of E2 and some of its metabolites on the genetic material, future in-depth mechanistic studies are required to clarify further the mechanism of E2-mediated carcinogenesis.

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