Imbalance of Estrogen Homeostasis in Kidney and Liver of Hamsters Treated with Estradiol:  Implications for Estrogen-Induced Initiation of Renal Tumors

Abstract

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.

A cohort study of reproductive and hormonal factors and renal cell cancer risk in women

“…A number of findings support the concept that pregnancy-associated hormonal changes, and, particularly, high oestrogen levels, may promote malignant changes by stimulating renal cell proliferation either directly or via growth factors (Concolino et al, 1993). These findings include the fact that administration of potent oestrogens has been shown to induce renal cancers in the Syrian hamster (Kirkman, 1959;Reznik-Schuller, 1979;Li and Li, 1990;Cavalieri et al, 2001), the presence of oestrogen and progesterone receptors in normal and malignant renal cells (Concolino et al, 1976;Ronchi et al, 1984), and the observed association with obesity, which provides a major source of oestrogen in postmenopausal women. However, the evidence supporting a role of exposure to endogenous or exogenous oestrogens in renal cell carcinogenesis is conflicting.…”

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

“…Experiments on estrogen metabolism [6][7][8][9][10], formation of DNA adducts [11][12][13][14][15][16][17], mutagenicity [17][18][19][20][21], cell transformation [22][23][24] and carcinogenicity [25][26][27][28] have led to the hypothesis that certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, react with DNA to cause the mutations leading to the initiation of cancer ( Fig. 1) [17].…”

Cytochrome P450 1A1 (CYP1A1) polymorphisms and breast cancer risk in Korean women

“…Cytochrome P450 1A1 (CYP1A1) is involved in the conversion of estrone (E1) and estradiol (E2) to 2-hydroxyestradiol (2-OHE1) (Cavalieri et al, 2001). CYP1A1 also has aryl hydrocarbon hydroxylase activity which is responsible for metabolizing polycyclic aromatic hydrocarbons (PAH) to aryl epoxides (Law, 1990).…”