Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3′,4′-quinone or enzyme-activated 3′-hydroxyhexestrol

• Published in: Steroids 2005, Vol.70 (1), p.37-45
• Main Authors: Saeed, Muhammad, Gunselman, Sandra J., Higginbotham, Sheila, Rogan, Eleanor, Cavalieri, Ercole
• Format: Article
• Language: English
• Subjects: Catechol quinones; Depurinating N3adenine adduct; Depurinating N7guanine adduct; Nonsteroidal synthetic estrogen
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2004.09.012

The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3–C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3′-OH-HES, which can be metabolically converted to the catechol quinone, HES-3′,4′-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3′,4′-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3′-OH-HES-6′-N7Gua by 1,4-Michael addition [Jan S-T, Devanesan PD, Stack DE, Ramanathan R, Byun J, Gross ML, et al. Metabolic activation and formation of DNAadducts of hexestrol,a synthetic nonsteroidal carcinogenic estrogen. Chem Res Toxicol 1998;11:412–9.]. We report here formation of the depurinating adduct 3′-OH-HES-6′-N3Ade by reaction of HES-3′,4′-Q with Ade by 1,4-Michael addition. The structure of the N3Ade adduct was established by NMR and MS. We also report here formation of the depurinating 3′-OH-HES-6′-N7Gua and 3′-OH-HES-6′-N3Ade adducts by reaction of HES-3′,4′-Q with DNA or by activation of 3′-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (