Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol: Implications for estrogen-induced initiation of renal tumors

Reaction of endogenous catechol estrogen quinones (CE-Q) with DNA may initi ate cancer by generation of oncogenic mutations. Treatment of male Syrian g olden hamsters with estrogens or 4-catechol estrogens (4-CE), but not 2-CE, induces kidney, but not liver, tumors. The hamster provides an excellent m odel for studying activation and deactivation (protection) of estrogen meta bolites in relation to formation of CE-Q. Several factors can unbalance est rogen homeostasis, thereby increasing the oxidative pathway leading to the carcinogenic CE-3,4-Q. Hamsters were injected with 8 mu mol of estradiol (E -2) and liver and kidney extracts were analyzed for 31 estrogen metabolites , conjugates, and depurinating DNA adducts by HPLC with electrochemical det ection. Neither liver nor kidney contained 4-methoxyCE, presumably due to t he known inhibition of catechol-O-methyltransferase by 2-CE. More O-methyla tion of 2-CE was observed in the liver and more formation of CE-Q in the ki dney. These results suggest less protective methylation of 2-CE and more pr onounced oxidation of CE to CE-Q in the kidney. To investigate this further , hamsters were pretreated with L-buthionine(SR)-sulfoximine to deplete glu tathione levels and then treated with E2. Compared to the liver, a very low level of CE and methoxyCE was observed in the kidney, suggesting little pr otective reductase activity. Most importantly, reaction of CE-3,4-Q with DN A to form the depurinating 4-hydroxyE(2)(E-1)1-N7Gua adducts was detected i n the kidney, but not in the liver. Therefore, tumor initiation in the kidn ey appears to arise from relatively poor methylation of 2-CE and poor reduc tase activity in the kidney, resulting in high levels of CE-Q. Thus, format ion of depurinating DNA adducts by CE-3,4-Q may be the first critical event in the initiation of estrogen-induced kidney tumors.