Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol

Implications for estrogen-induced initiation of renal tumors

Ercole Cavalieri, S. Kumar, R. Todorovic, S. Higginbotham, A. F. Badawi, Eleanor G Rogan

Research output: Contribution to journalArticle

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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 μmol 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.

Original languageEnglish (US)
Pages (from-to)1041-1050
Number of pages10
JournalChemical Research in Toxicology
Volume14
Issue number8
DOIs
StatePublished - Sep 11 2001

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Catechol Estrogens
Cricetinae
Liver
Tumors
Estradiol
Estrogens
Homeostasis
Kidney
Quinones
Methylation
Neoplasms
DNA Adducts
Metabolites
Oxidoreductases
Catechol O-Methyltransferase
DNA
Glutathione
Liver Extracts
Chemical activation
Mesocricetus

ASJC Scopus subject areas

  • Toxicology

Cite this

Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol : Implications for estrogen-induced initiation of renal tumors. / Cavalieri, Ercole; Kumar, S.; Todorovic, R.; Higginbotham, S.; Badawi, A. F.; Rogan, Eleanor G.

In: Chemical Research in Toxicology, Vol. 14, No. 8, 11.09.2001, p. 1041-1050.

Research output: Contribution to journalArticle

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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 μmol 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.",
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