CYP450- and COMT-Derived Estradiol Metabolites Inhibit Activity of Human Coronary Artery SMCs

Dubey, Raghvendra K.; Gillespie, Delbert G.; Zacharia, Lefteris C.; Barchiesi, Federica; Imthurn, Bruno; Jackson, Edwin K.

doi:10.1161/01.hyp.0000048862.28501.72

Cited by 52 publications

(54 citation statements)

References 21 publications

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“…Previously, using pharmacological agents to block or induce the conversion of estradiol to hydroxyestradiols and methoxyestradiols, we provided indirect evidence that methoxyestradiols mediate the vascular antimitogenic effects of estradiol. 5,13 We found similar evidence for this hypothesis in cardiac fibroblasts 14 and glomerular mesangial cells. 15 Although use of pharmacological agents provides evidence supporting our hypothesis, direct evidence for the role of methoxyestradiols as mediators of the ER-independent antimitogenic actions of estradiol is lacking.…”

supporting

confidence: 79%

“…13 We have demonstrated that ICI182,780 blocks the vascular antimitogenic effects of estradiol only at concentrations that inhibit the metabolism of estradiol to hydroxyestradiols. 5,13 The above findings suggest that the antiproliferative actions of estradiol are ER-independent. Because estradiol is sequentially metabolized to hydroxyestradiols by CYP450s and hydroxyestradiols are methylated to methoxyestradiols by COMT, we hypothesize that methoxyestradiols mediate the antiproliferative actions of estradiol on SMCs via ER-independent mechanisms.…”

mentioning

confidence: 93%

“…13 Because both CYP450s and COMT are expressed in SMCs, 13 estradiol can be locally converted to methoxyestradiols. In WT SMCs, the inhibitory effects of estradiol are significantly enhanced by phenobarbital, a CYP450 inducer, 13 and blocked by 1-aminobenzotriazole, a CYP450 inhibitor. 5,13 Moreover, the inhibitory effects of estradiol and 2-hydroxyestradiol are abolished by OR-486 (a COMT inhibitor).…”

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confidence: 99%

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Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

et al. 2003

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Background-Studies using pharmacological agents suggest but do not prove that the antimitogenic effects of estradiol are caused by conversion of estradiol to hydroxyestradiols (mediated by CYP450s) followed by methylation of hydroxyestradiols to methoxyestradiols (mediated by catechol-O-methyltransferase, COMT). Methods and Results-To test this hypothesis more rigorously, we used aortic smooth muscle cells (SMCs) from mice lacking COMT (COMT-KO). Wild-type (WT) but not COMT-KO SMCs efficiently converted 2-hydroxyestradiol to 2-methoxyestradiol. Both WT and COMT-KO SMCs expressed estrogen receptors. Estradiol and 2-hydroxyestradiol concentration-dependently inhibited serum-induced DNA synthesis, cell numbers, and collagen synthesis in WT but not COMT-KO SMCs. 2-Methoxyestradiol inhibited DNA synthesis, cell numbers, and collagen synthesis in both WT and COMT-KO SMCs. Conclusions-These data provide strong evidence that the vascular antimitogenic effects of estradiol are estrogen receptor-independent and involve the sequential conversion of estradiol to hydroxyestradiols and then to methoxyestradiols. (Circulation. 2003;108:2974-2978.)Key Words: coronary disease Ⅲ hormones Ⅲ metabolism Ⅲ muscle, smooth Ⅲ receptors S eventeen ␤-estradiol (estradiol) inhibits the growth of vascular smooth muscle cells (SMCs), even in mice lacking estrogen receptors (ERs). 1-3 Because methoxyestradiols (major endogenous metabolites of estradiol with no affinity for ERs) inhibit growth of cancer cells, 4 it is feasible that the vascular antimitogenic effects of estradiol are mediated by methoxyestradiols. Using pharmacological agents, previous studies demonstrate that metabolism of estradiol to hydroxyestradiols by CYP450 followed by methylation of hydroxyestradiols by catechol-O-methyltransferase (COMT) to form methoxyestradiols is critical for estradiol-induced inhibition of SMC growth. 5 In the present study, we use aortic SMCs from COMT-knockout (COMT-KO) mice 6 that express ERs but lack methylation capability to test our hypothesis that the vascular antimitogenic effects of estradiol are mediated via an ER-independent mechanism involving formation of methoxyestradiols. MethodsCOMT-KO mice were developed by Dr Karayiorgou. 6 Aortic SMCs were cultured from male mice by the explant technique. SMC purity was tested by immunostaining with SMC-specific antibodies as described previously. 7 Cells in passage 2 were used.3 H]proline incorporation, and cell proliferation were conducted as previously. 7 The absence of COMT was confirmed by incubating SMCs from wild-type (WT) and COMT-KO mice for 2 hours with 2-hydroxyestradiol (2 mol/L) and analyzing 2-hydroxyestradiol/2-methoxyestradiol by high-performance liquid chromatography, as previously. 8 ER␣ and ER␤ expression were analyzed by Western blots. 9 Experiments were conducted in triplicate (repeated 3 or 4 times). Results are expressed as meanϮSEM. Statistical analyses were performed with ANOVA and Fisher's least significant difference test. A value of PϽ0.05 was considered statistically ...

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confidence: 79%

mentioning

confidence: 93%

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confidence: 99%

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Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

et al. 2003

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“…Sequential metabolism of estradiol to catecholestradiols and ultimately to methoxyestradiols is responsible for the antimitogenic effects of estradiol on vascular SMCs, 61 cardiac fibroblasts, 62 and glomerular mesangial cells. 63 Importantly, these effects of estradiol appear to be ER-independent.…”

Section: Type Of Estrogenmentioning

confidence: 99%

“…63 Importantly, these effects of estradiol appear to be ER-independent. [61][62][63] The antimitogenic effects of estradiol are lost in aortic SMCs cultured from catecholamine-O-methyltransferase (COMT) knockout mice that cannot convert estradiol to 2-methoxyestradiol. 64 Increased proliferation of SMCs, cardiac fibroblasts, and mesangial cells lead to hypertension, vascular disease, left ventricular hypertrophy, and glomerulosclerosis.…”

Section: Type Of Estrogenmentioning

confidence: 99%

Hormone Replacement Therapy and Cardiovascular Disease

et al. 2004

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Abstract-Observational studies in humans and experimental studies in animals and isolated cells supported the widely held belief that hormone replacement therapy protects the cardiovascular system from disease. To nearly everyone's astonishment, the Women's Health Initiative Study and the Heart and Estrogen/Progestin Replacement Study overturned the conclusion that hormone replacement therapy protects the cardiovascular system and, in fact, supported the opposite view that such therapy may actually increase the risk of cardiovascular disease. Observational Studies Suggest HRT Has Beneficial Cardiovascular EffectsIn modern societies, cardiovascular disease is the main cause of morbidity and mortality in men and women. Women, however, are comparatively spared. For example, in people younger than age 65 years, the prevalence of coronary heart disease (CHD) is several-fold higher in men. 3,4 Although CHD prevalence increases with age in both genders, before the age of 65 years the relationship between age and CHD prevalence is shifted rightward by 5 years in women; 5,6 compared with postmenopausal women, CHD deaths are rare in premenopausal women. 7 Autopsy studies demonstrated increased CHD in oophorectomized young women, 8 and several studies demonstrated an increased risk of cardiovascular disease in women with bilateral oophorectomy without HRT compared with those receiving HRT. 9,10 Women with natural early-onset menopause who did not use HRT had a greater likelihood for CHD compared with age-matched premenopausal women. 9,11 Also, studies reported an inverse relationship between age at natural menopause and mortality from CHD 12,13 and carotid atherosclerosis. 14 Bush et al demonstrated that HRT was associated with reduced all-cause mortality in postmenopausal women, 15 primarily because of favorable effects on high-density lipoprotein. 16 Barrett-Connor and Bush 8 reported that many, but not all, cross-sectional and prospective studies demonstrated a statistically significant reduction in CHD in women taking HRT, and Grady et al 17 presented a meta-analysis of published observational studies and reported that HRT was associated with one-third less fatal CHD. An up-to-date meta-analysis of 25 observational studies conducted between 1976 and 1996 showed that the relative risk for CHD in women who ever used HRT compared with never users was 0.70. 18 The Nurses' Health Study was a comprehensive investigation conducted in 121 700 female nurses aged 30 to 55 years. In the latest report, compiled with data from 70 533 postmenopausal women followed-up for 20 years, the overall risk of CHD in current users of HRT was reduced, with a relative risk of 0.61 after adjustment for age and cardiovascular risk factors. 19

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Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

Jhajra

Varkhede

Ahire

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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Drug‐metabolizing enzymes (DMEs) are primarily expressed in the liver but their role in the extrahepatic tissues such as gastrointestinal tract (GIT), pulmonary, excretory, nervous, cardiovascular system, and skin cannot be neglected. Generally, the expression of DMEs in extrahepatic tissues is quantitatively lower than that in the liver, but there are a few enzymes such as CYP1A1, CYP1B1, CYP2F1, and CYP2U1 that are more abundant in extrahepatic organs. As many extrahepatic organs are portals for administered drugs, DMEs expressed in these organs can be responsible for significant metabolism, leading to first‐pass effects and lower bioavailability. Extrahepatic DMEs are also involved in bioactivation of prodrugs and formation of reactive metabolites that may interact with cellular components, resulting in organ‐specific toxicity. Activity and expression of extrahepatic DMEs is often altered by coadministered drugs, leading to drug–drug interactions. Expression of DMEs in living beings affected by a host of environmental and genetic factors such as genetic polymorphism, age, gender, pathophysiological conditions, inborn errors in metabolism, food habits, and environmental pollutants, contributing to varied drug effects and idiosyncratic toxicities.

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CYP450- and COMT-Derived Estradiol Metabolites Inhibit Activity of Human Coronary Artery SMCs

Cited by 52 publications

References 21 publications

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

Hormone Replacement Therapy and Cardiovascular Disease

Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

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