Metabolic Clearance Rate and Conversion Ratios of [3H]2-Hydroxyestrone in Normal Men*

Longcope, Christopher; Femino, Andrea M.; Flood, Charles A.; Williams, Keith R.

doi:10.1210/jcem-54-2-374

Cited by 24 publications

(5 citation statements)

References 23 publications

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“…gens were analyzed in several independent studies, catechol estrogens accounted for majority of total tissue estrogens, and their levels were significantly higher than levels of the classical estrogen hormones (37,38). In plasma, catechol estrogen concentrations are fairly low and rarely exceed 500 pg/ml levels in premenopausal women (24,39) because of high clearance of hydroxylated estrogens from the blood through further metabolism to metoxyestrogens (40). High clearance rates and local tissue synthesis of catechol estrogens are consistent with the idea that effects of these compounds are local and paracrine in nature.…”

Section: Catechol Estrogens Activate Trpa1mentioning

confidence: 99%

Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel

Chen

Cerne

et al. 2019

Journal of Biological Chemistry

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Edited by Qi-Qun Tang Estrogen hormones play an important role in controlling glucose homeostasis and pancreatic ␤-cell function. Despite the significance of estrogen hormones for regulation of glucose metabolism, little is known about the roles of endogenous estrogen metabolites in modulating pancreatic ␤-cell function. In this study, we evaluated the effects of major natural estrogen metabolites, catechol estrogens, on insulin secretion in pancreatic ␤-cells. We show that catechol estrogens, hydroxylated at positions C2 and C4 of the steroid A ring, rapidly potentiated glucose-induced insulin secretion via a nongenomic mechanism. 2-Hydroxyestrone, the most abundant endogenous estrogen metabolite, was more efficacious in stimulating insulin secretion than any other tested catechol estrogens. In insulinsecreting cells, catechol estrogens produced rapid activation of calcium influx and elevation in cytosolic free calcium. Catechol estrogens also generated sustained elevations in cytosolic free calcium and evoked inward ion current in HEK293 cells expressing the transient receptor potential A1 (TRPA1) cation channel. Calcium influx and insulin secretion stimulated by estrogen metabolites were dependent on the TRPA1 activity and inhibited with the channel-specific pharmacological antagonists or the siRNA. Our results suggest the role of estrogen metabolism in a direct regulation of TRPA1 activity with potential implications for metabolic diseases.

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Section: Catechol Estrogens Activate Trpa1mentioning

confidence: 99%

Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel

Chen

Cerne

et al. 2019

Journal of Biological Chemistry

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“…Kinetic studies have shown that 2-hydroxyestrone is metabolised very rapidly in the blood, more rapidly than other known natural steroids (4). The conversion takes place in the blood by the enzyme catechol orthomethyltransferase (COMT) which is found in erythrocytes (4).…”

Section: Most Important Estradiol Metabolitesmentioning

confidence: 99%

“…The conversion takes place in the blood by the enzyme catechol orthomethyltransferase (COMT) which is found in erythrocytes (4). Evidence that there are differences in the biological behaviour of the methylated and non-methylated forms has been obtained in studies which revealed the anti-oestrogenic actions of 2-hydroxyestrone after preventing methylation (5); it suppressed the growth of the breast cancer cell line MCF-7 (6, 7).…”

Section: Most Important Estradiol Metabolitesmentioning

confidence: 99%

Are estradiol metabolites involved in gynaecological carcinogenesis?

Seeger

Mueck

2009

Hormone Molecular Biology and Clinical Investigation

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Certain estradiol metabolites are biologically active, sometimes several times more potent than their parent substance. Highly sophisticated laboratory methods allow us to understand oestrogenic effects as a net effect of the corresponding metabolite pattern. Currently, research is focused on the anticancerogenic effects of 2-hydroxyestrone and particularly 2-methoxyestradiol, as well as the possible carcinogenic properties of 4-hydroxyoestrogens and 16α-hydroxyestrone. The clinical relevance of these activities, demonstrated in in-vitro and animal experiments, remains unclear - it is proven, however, that the metabolite production can be altered in certain malignancies such as endometrial-, breast- and cervical carcinoma. Clinical studies, including our studies, have demonstrated a negative correlation between the ratio of 2-hydroxyestrone to 16α-hydroxyestrone and breast cancer risk. However, the design and interpretation of such studies should consider factors influencing metabolic pattern such as diet, physical activity, smoking, as well as internal diseases and certain drugs.

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“…Estradiolmetaboliten mit möglichen Wirkungen auf das Tumorwachstum 2-Hydroxyestron Kinetische Untersuchungen ergaben, dass 2-Hydroxyestron sehr schnell aus dem Blut verschwindet, schneller als alle anderen natürlichen Steroide [61,62,72]. Die Umwandlung erfolgt bereits im Blut durch das Enzym Catechol-ortho-methyltransferase (COMT) der Erythrozyten [62].…”

Section: Wichtigste Estradiolmetaboliteunclassified

Östrogenabhängige Neoplasien - welche Bedeutung haben Estradiolmetaboliten

Mueck

Seeger²,

Th³

2003

Zentralbl Gynakol

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Estradiol can be metabolized to substances eliciting different, partly opposite effects even at low concentrations as shown in own investigations, e. g., regarding (anti)angiogenic actions. Specific anticancerogenic effects are ascribed to 2-hydroxyestrone and particularly 2-methoxyestradiol. In contrast, 16alpha-hydroxyestrone and the 4-hydroxyestrogens may be genotoxic under certain circumstances. Furthermore there are indications that endogenous production of proliferation-stimulating metabolites is raised in some cancers. Especially the urinary excretion of 2-hydroxyestrone to 16alpha-hydroxyestrone was investigated showing in own and other clinical studies a lower ratio in postmenopausal women with breast cancer. Research is ongoing inasfar the determination of estradiol metabolites also in blood or directly in the breast tissue by means of sensitive laboratory methods may allow predictive statements. However, it has be to consider that estradiol metabolism can be influenced by external factors such as nutrition, smoking, sports and drugs such as L-thyroxine and H2-antagonists. We were able to demonstrate that estradiol metabolism during estradiol treatment depends on the application mode and might be differently influenced by addition of the various progestins. Whether the investigation of gene polymorphism of enzymes, which are involved in estradiol metabolism, may be helpful for the assessment or treatment of risk patients, to our opinion needs further research.

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Metabolic Clearance Rate and Conversion Ratios of [3H]2-Hydroxyestrone in Normal Men*

Cited by 24 publications

References 23 publications

Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel

Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel

Are estradiol metabolites involved in gynaecological carcinogenesis?

Östrogenabhängige Neoplasien - welche Bedeutung haben Estradiolmetaboliten

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