Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen sulfoconjugation previously was reported in normal endometrium and in RL95-2 cells, a cell line derived from a human endometrial cancer maintained in continuous in vitro culture. In the present study the estrogen sulfurylation activity in the cytosolic fraction of RL95-2 cells was characterized using [3H]estrone as substrate. Estrone sulfate was separated from unreacted estrone by thin layer chromatography. Activity was proportional to cytosol concentration, with a pH optimum at pH 8. There was marked temperature dependence between 24 and 40 C. The apparent Km for estrone conjugation was 3.6 nM, with a maximum velocity of 135 fmol/micrograms DNA . h. No complex kinetic behavior was found at estrone concentrations up to 1 microM. The apparent Km for the cosubstrate 3'-phosphoadenosine 5'-phosphosulfate was 0.6 microM. Inhibition experiments demonstrated that the sulfurylating activity studied under these conditions was specific for estrogens. Only estradiol and estriol, in addition to estrone itself, inhibited conjugation to any significant degree. Dehydroepiandrosterone had only 1% the inhibitory activity of estrone. Other androgens, corticoids, progestins, phenols, nonsteroidal estrogens and antiestrogens, and bile acids had no significant effects on the sulfurylation of estrone. An estrogen-sulfoconjugating activity with the characteristics of estrogen sulfotransferase (EST) was demonstrated in RL95-2 cells. The Km of EST for estrone in the RL95-2 cells closely approximated the value reported for the enzyme in normal endometrium. The affinity of EST for estrogens is within the range of the Kd of estrogen receptor and of the physiological concentrations of estrogens reported in the endometrium, suggesting that EST could serve as a regulator of intracellular estrogen levels.
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PMID:Characterization of cytosolic estrogen sulfotransferase from RL95-2 endometrial cancer cells. 659 68

An increased incidence of endometrial cancer has been reported in breast cancer patients taking tamoxifen (TAM) and in healthy women participating in the TAM chemoprevention trials. Because TAM-DNA adducts are mutagenic and detected in the endometrium of women treated with TAM, TAM adducts are suspected to initiate the development of endometrial cancer. Treatment with TAM has been known to promote hepatocarcinoma in rats, but toremifene (TOR), a chlorinated TAM analogue, did not. TAM adducts are primarily formed via sulfonation of the alpha-hydroxylated TAM metabolites. To explore the mechanism of the lower genotoxicity of TOR, the formation of DNA adducts induced by TOR metabolites was measured using (32)P-postlabeling/ high-performance liquid chromatography analysis and compared with that of TAM metabolites. When alpha-hydroxytoremifene was incubated with DNA, 3'-phosphoadenosine 5'-phosphosulfate, and either rat or human hydroxysteroid sulfotransferase, the formation of DNA adducts was two orders of magnitude lower than that of alpha-hydroxytamoxifen. alpha-hydroxytoremifene was a poor substrate for rat and human hydroxysteroid sulfotransferases. In addition, the reactivity of alpha-acetoxytoremifene, a model activated form of TOR, with DNA was much lower than that of alpha-acetoxytamoxifen. Thus, TOR is likely to have lower genotoxicity than TAM. TOR may be a safer alternative by avoiding the development of endometrial cancer.
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PMID:Mechanism of lower genotoxicity of toremifene compared with tamoxifen. 1135 7

Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of alpha-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, alpha-OHTAM, and either 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of alpha-hydroxylated TAM and its metabolites.
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PMID:Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers. 1609 24