Diethylstilbestrol

DES is a diphenolic compound synthesized in 1938 [53] in the search for an orally effective estrogen. It matches E2 in terms of its affinity to the estrogen receptors and is superior in terms of oral efficacy. DES contributed much to the present concern about carcinogenic effects of estrogens, as it proved to be the culprit of a rare form of vaginal and cervical tumors discovered in 1970 by Herbst et al. [54] and was shown to be a potent carcinogen in several animal models including the Syrian hamster kidney [55] and the neonatal mouse uterus [56]. Despite the efforts of several laboratories, its mechanism of tu-morigenesis is still poorly understood. The formation of reactive metabolites has been demonstrated and their involvement in DES-mediated carcinogenesis proposed as early as 1975 [57,58]. Today, several pathways for the metabolic activation of DES are discussed; for review see [6,9,10]. The best studied route for the generation of reactive metabolites is depicted in Fig. 7 together with the associated biochemical effects. Briefly, DES can be oxidized by cytochrome P450 or peroxidases to its 4',4"-semiquinone and 4',4"-quinone, which tautomerizes spontaneously to Z,Z-dienestrol. This metabolic sequence has been shown with microsomes from various organs and is believed to occur in target tissues of DES carcinogenicity. The semiquinone intermediate may reduce oxygen to superoxide radicals and thus give rise to ROS, which in turn causes lipid peroxidation and oxidative DNA damage. Moreover, DNA may be adducted by the electrophilic DES-4',4"-quinone and by reactive products of lipid peroxidation. Both types of adducts have been demonstrated by the 32P-postlabeling technique in the Syrian hamster kidney, together with oxidized DNA bases. Other pathways of DES metabolism proposed for metabolic activation are the formation of the catechol 3-hydroxy-DES with subsequent oxidation to the respective ortho-semiquinone and -quinone in analogy to the activation of E2 and EN discussed earlier (see Sect. 2.1), and a-hydroxylation at C-2 or C-5 of the ethyl groups to yield an allylic alcohol which becomes reactive after sulfate conjugation [59], as described for tamoxifen (see Sect. 3.1). By the same token, it can be speculated that 1-hydroxy-Z,Z-dienestrol, which is also an allylic alcohol, can be activated by sulfation. Thus, DES can cause DNA lesions by various mechanisms. It remains to be demonstrated which are relevant for its carcinogenic effects.

Sulfation?

Lipid

Peroxidation

Covalent DNA Adducts

Oxidative DNA Damage

1 -hydroxy- Z,Z-dienestrol

DES-4',4"-semiquinone

DES-4',4"-quinone

Z,Z-dienestrol

Colchicine-Like MTP Binding

Covalent MTP Binding

Non-Covalent MTP Binding

Inhibition of MT Assembly

Induction of Aneuploidy

Fig. 7. Proposed metabolic activation and genotoxic effects of DES

In addition to damaging DNA, DES has been shown to give rise to numerical and structural chromosomal aberrations in cultured cells [60] and in target organs of DES carcinogenesis, e.g., the Syrian hamster kidney [61].As depicted in Fig. 7, DES and several of its oxidative metabolites affect microtubule proteins (MTP) through different mechanisms [17]. Binding to MTP inhibits the assembly of microtubules and disrupts the mitotic spindle, thereby causing aneu-ploidy. DES itself binds to the major MTP, the heterodimer of a- and b-tubulin, in a colchicine-like manner. The binding of DES-4',4"-quinone and Z,Z-diene-strol to MTP has been less well characterized, but both agents inhibit cell-free MT assembly [62].

Induction of aneuploidy represents an important mechanism of neoplastic cell transformation [63,64]. DES was shown to induce near-diploid aneuploidy as well as morphological and neoplastic transformation of primary Syrian hamster embryo (SHE) fibroblasts in the absence of detectable gene mutations or DNA damage [60, 65, 66]. However, gene mutations were observed in the same cells with DES in the presence of exogenous metabolic activation [67]. Both aneuploidy induction and DNA adduct formation correlated with DES-in-duced cell transformation and may be important in the mechanism of DES carcinogenesis [65].

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