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

Chem Res Toxicol. 2001 Aug;14(8):1041-50. doi: 10.1021/tx010042g.


Reaction of endogenous catechol estrogen quinones (CE-Q) with DNA may initiate cancer by generation of oncogenic mutations. Treatment of male Syrian golden hamsters with estrogens or 4-catechol estrogens (4-CE), but not 2-CE, induces kidney, but not liver, tumors. The hamster provides an excellent model for studying activation and deactivation (protection) of estrogen metabolites in relation to formation of CE-Q. Several factors can unbalance estrogen homeostasis, thereby increasing the oxidative pathway leading to the carcinogenic CE-3,4-Q. Hamsters were injected with 8 micromol of estradiol (E(2)), and liver and kidney extracts were analyzed for 31 estrogen metabolites, conjugates, and depurinating DNA adducts by HPLC with electrochemical detection. Neither liver nor kidney contained 4-methoxyCE, presumably due to the known inhibition of catechol-O-methyltransferase by 2-CE. More O-methylation of 2-CE was observed in the liver and more formation of CE-Q in the kidney. These results suggest less protective methylation of 2-CE and more pronounced oxidation of CE to CE-Q in the kidney. To investigate this further, hamsters were pretreated with L-buthionine(S,R)-sulfoximine to deplete glutathione levels and then treated with E(2). Compared to the liver, a very low level of CE and methoxyCE was observed in the kidney, suggesting little protective reductase activity. Most importantly, reaction of CE-3,4-Q with DNA to form the depurinating 4-hydroxyE(2)(E(1))-1-N7Gua adducts was detected in the kidney, but not in the liver. Therefore, tumor initiation in the kidney appears to arise from relatively poor methylation of 2-CE and poor reductase activity in the kidney, resulting in high levels of CE-Q. Thus, formation of depurinating DNA adducts by CE-3,4-Q may be the first critical event in the initiation of estrogen-induced kidney tumors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinogens / adverse effects*
  • Carcinogens / metabolism
  • Cell Transformation, Neoplastic
  • Cricetinae
  • DNA Adducts
  • Estradiol / adverse effects*
  • Estrogens / metabolism*
  • Estrogens, Catechol / adverse effects*
  • Estrogens, Catechol / metabolism
  • Homeostasis
  • Kidney / chemistry
  • Kidney Neoplasms / etiology*
  • Liver / chemistry
  • Male
  • Mesocricetus
  • Methylation
  • Oxidoreductases / metabolism
  • Quinones / chemistry*


  • Carcinogens
  • DNA Adducts
  • Estrogens
  • Estrogens, Catechol
  • Quinones
  • Estradiol
  • Oxidoreductases