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 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.
Cavalieri
E L
EL
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA. ecavalie@unmc.edu
Kumar
S
S
Todorovic
R
R
Higginbotham
S
S
Badawi
A F
AF
Rogan
E G
EG
D000818:Animals; D002273:Carcinogens / Q000009:adverse effects* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D018736:DNA Adducts; D004958:Estradiol / Q000009:adverse effects*; D004967:Estrogens / Q000378:metabolism*; D002393:Estrogens, Catechol / Q000009:adverse effects* / Q000378:metabolism; D006706:Homeostasis; D007668:Kidney / Q000737:chemistry; D007680:Kidney Neoplasms / Q000209:etiology*; D008099:Liver / Q000737:chemistry; D008297:Male; D008647:Mesocricetus; D008745:Methylation; D010088:Oxidoreductases / Q000378:metabolism; D011809:Quinones / Q000737:chemistry*
D002273:Carcinogens; D018736:DNA Adducts; D004967:Estrogens; D002393:Estrogens, Catechol; D011809:Quinones; D004958:Estradiol; D010088:Oxidoreductases