An Estrogen-Nucleic Acid Adduct. Electroreductive Intermolecular Coupling of 3,4-Estrone-o-quinone and Adenine

Abstract

Estrogens have been shown to induce mammary, pituitary, cervical, and uterine tumors in rats, mice, and guinea pigs.1 Estradiol and other estrogens induce renal carcinoma in 80-100% of Syrian hamsters within 6-8 months.* 12 Although the exact mechanism for carcinogenesis induced by estrogenic compounds is not fully understood, it is generally believed that metabolic activation of estradiol leading to the formation of catechol estrogens is a prerequisite for its genotoxic activity.3 It has been proposed that the steroid estrogens may generate reactive intermediates, particularly arene oxides4 and quiñones/ semiquinones, during their metabolism in analogy to the metabolism of aromatic polycyclic hydrocarbons which are known to be implicated in carcinogenesis.5 Thus, the estrogen o-quinones/semiquinones produced by the oxidation of catechol estrogens by phenol oxidase,6 prostaglandin H synthetase,7 and cytochrome P-450 oxidase8 have the potential to be cytotoxic and genotoxic. Studies in our laboratories have shown that 3,4estronequinone (3,4-EQ), which can "redox-cycle" leading to the formation of hydrogen peroxide, the hydroxyl radical, and the semiquinone of 3,4-EQ,9b was capable of inducing exclusively single strand DNA breaks/alkali-labile sites in a human breast cancer cell line.93 Although hydroxyl radical production was found to correlate with 3,4-EQ-induced DNA damage,9c the production of hydrogen peroxide and the hydroxyl radical may only be an indicator of the metabolism of 3,4-EQ to a DNA-damaging species. Thus, two potential mechanisms may be involved in the carcinogenicity/toxicity of estrogen quiñones: ary latí on of macromolecules including proteins, DNA and RNA, and generation of reactive oxygen species (ROS). While Michael addition products from reaction of amino acid nucleophiles are well documented,10 *many previous attempts at

Some Applications of Electrochemistry in Biomedical Chemistry. Emphasis on the Correlation of Electrochemical and Bioactive Properties

“…There are several main classes of electron transfer agents, some of them already mentioned: nitroaromatics (6, 8-10, 13-14) (or their reduced forms, 15), quinones (5, 11-12) (or phenolic precursors 21, 23, 24), aza compounds (or azo dyes), iminium ions [or imines, aromatic (25,26) and aliphatic N-oxides, triarylmethane dyes (27), Nheterocyclic salts (28)] and metal complexes (1, 29) or metal quelators. In the present case, emphasis will be held on nitroaromatics and quinones.…”

Characterisation of estrone–nucleic acid adducts formed by reaction of 3,4‐estrone‐o‐quinone with 2′‐deoxynucleosides/deoxynucleotides using capillary liquid chromatography/electrospray ionization mass spectrometry

“…Earlier studies showed that, under electrochemical reductive conditions, 3,4‐E 1 Q in dimethylformamide (DMF) reacted to form an adduct with adenine (3,4‐E 1 Q‐1‐C 8 Ade) 20. This procedure, being cumbersome for large‐scale reactions, was replaced by a chemical reductive process involving sodium dithionite in dry DMF to generate the 3,4‐estrone semiquinone radical anion and finally to synthesise adducts with the nucleobases and deoxynucleosides 21,22.…”

Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development

“…The covalent binding of oestrogen quinone reactive intermediates to guanine and adenine nucleic acid bases has also been investigated in cell-free test systems and in rats and hamsters in vivo (Table 11) (Abul-Hajj et al, 1995;Stack et al, 1996;Cavalieri et al, 1997;Roy and Abul-Hajj, 1997;Shen et al, 1997Shen et al, , 1998. Quinone intermediates of 4hydroxylated oestrogens have been shown to form unstable DNA adducts, which decompose and form potentially mutagenic apurinic sites, whereas 2-hydroxylated oestrogen metabolites generate more stable DNA adducts .…”