Hk. Bhat et al., REGULATION OF THE FORMATION OF THE MAJOR DIETHYLSTILBESTROL DNA ADDUCT AND SOME EVIDENCE OF ITS STRUCTURE, Carcinogenesis, 15(10), 1994, pp. 2137-2142
Diethylstilbestrol (DES) induces kidney tumors in hamsters, In previou
s studies, DES has been shown by P-32-postlabeling analysis to bind co
valently to DNA in vivo and in vitro and DES-DNA adduct formation has
been suggested to play a key role in DES-induced carcinogenicity. In t
his study, we have examined the influence of the dose of DES, age of a
nimals and organ specificity on adduct formation in hamsters. In addit
ion, we examined the characteristics of DES-DNA adduct formation in vi
tro and the structure of the major adduct. DES-DNA adducts were detect
ed in liver and kidney of hamsters treated with at least 20 mg/kg DES.
Adduct concentrations were higher at higher doses or in older compare
d to younger animals. The covalent binding of DES to DNA catalyzed by
hamster liver microsomes required cumene hydroperoxide as cofactor, wh
ereas with NADPH, adducts were barely detectable, presumably because t
he reactive metabolic intermediate DES quinone was reduced to DES. The
major DES-DNA adduct formed in vitro was purified by semipreparative
and analytical high pressure liquid chromatography. It is concluded th
at DES-DNA adducts are formed from DES quinone at very low rates in vi
tro and occur at low levels in vivo, even when hamsters receive very l
arge doses of DES. The dependence of DES-DNA adduct concentrations in
vitro on organic hydroperoxide cofactors required for cytochrome P450-
mediated DES quinone formation indicates that stilbene-DNA adduction m
ay occur only under conditions of oxidative stress.