• 대한의생명과학회지
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• 제24권3호
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• pp.143-149
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• 2018

Excessive exposure to estrogens is the most important risk factor for the development of hormone-sensitive cancers, especially breast cancer. Estrogen stimulates the expression of genes and proteins involved in cell proliferation by binding to estrogen receptor (ER). Another possible mechanism of ER-independent carcinogenicity of estrogens is based on the hydroxylation of estradiol resulting in the formation of catechol estrogens. Catechol estrogen 4-hydroxyestradiol ($4-OHE_2$) is further oxidized to catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. Evidence increasingly supports the critical role of $4-OHE_2$ in hormonal carcinogenesis via DNA adduct formation or production of reactive oxygen species, which finally contribute to the transformation of normal mammary epithelial cells and the enhanced growth of breast cancer cells. It is also reported that the level of $4-OHE_2$ or its quinones is highly up-regulated in urine or tissues of breast cancer patients. Thus, we highlight the oncogenic roles of $4-OHE_2$ in catechol estrogen-induced breast carcinogenesis.

• BMB Reports
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• 제44권7호
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• pp.423-434
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• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• 대한의생명과학회지
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• 제25권1호
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• pp.1-6
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• 2019

The hydroxylation of estradiol results in the formation of catechol estrogens such as 2-hydroxyestradiol ($2-OHE_2$) and 4-hydroxyestradiol ($4-OHE_2$). These catechol estrogens are further oxidized to quinone metabolites by peroxidases or cytochrome P450 (CYP450) enzymes. Catechol estrogens contribute to hormone-induced carcinogenesis by generating DNA adducts or reactive oxygen species (ROS). Interestingly, many of the natural products found in living organisms have been reported to show protective effects against carcinogenesis induced by catechol estrogens. Although some compounds have been reported to increase the activity of catechol estrogens via oxidation to quinone metabolites, many natural products decreased the activity of catechol estrogens by inhibiting DNA adduct formation, ROS production, or oxidative cell damage. Here we focus specifically on the chemopreventive effects of these natural compounds against carcinogenesis induced by catechol estrogens.

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2003년도 추계학술대회
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• pp.188-188
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• 2003

• 한국독성학회:학술대회논문집
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• 한국독성학회 2003년도 추계학술대회
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• pp.188-188
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• 2003

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototype of halogenated aromatic hydrocarbons, is a persistent environmental contaminant and one of the most powerful tumor promoters. The molecular mechanism underlying induction of tumor promotion by TCDD has not been elucidated.(omitted)

• Archives of Pharmacal Research
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• 제20권5호
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• pp.454-458
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• 1997

Two human liver UDP-glucuronosyltransferase cDNA clones, HLUG25 and UDPGTh2 were previously shown to encode isozymes active in the glucuronidation of hyodeoxycholic acid (HDCA) and certain estrogen derivatives (e.g., estriol and 3,4-catechol estrogens), respectively. in this study we have found that the UDPGTh2-encoded isoform (UDPGTh2) and HLUG25-encoded isoform (UDPGThl) have parallel aglycone specificities. When expressed in COS 1 cells, each isoform metabolized three types of dihydroxy- or trihydroxy-substituted ring structures, including the 3,4-catechol estrogen (4-hydroxyestrone), estriol, 17-epiestriol, and HDCA, but the UDPGTh2 isozyme was 100-fold more efficient than UDPGTh1. UDPGTh1 and UDPGTh2 were 86% identical overall (76 differences out of 528 amino acids), including 55 differences in the first 300 amino acids of the amino terminus, a domain which conferred the substrate specificity. The data indicated that a high level of conservation in the amino terminus was not required for the preservation of substrate selectivity. Analysis of glucuronidation activity encoded by UDPGTh1/UDPGTh2 chimeric cDNA constructed at their common restriction sites, Sac I (codon 297), Nco I (codon 385), and Hha I (codon 469), showed that nine amino acids between residues 385 and 469 were important for catalytic efficiency, suggesting that this region represented a domain which was critical for the catalysis but distinct from that responsible for aglycone-selection. These data indicate that UDPGTh2 is a primary isoform responsible for the detoxification of the bile salt intermediate as well as the active estrogen intermediates.

• Asian Pacific Journal of Cancer Prevention
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• 제15권18호
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• pp.7941-7945
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• 2014

Catechol-O-methyltransferase (COMT) is involved in estrogen metabolism and is vital to estrogen-induced carcinogenesis, including that of ovarian cancer. Although many recent epidemiologic studies have investigated associations between the COMT rs4680 polymorphism and ovarian cancer risk, the results remain inconclusive. We therefore performed a meta-analysis to derive a more precise estimate of associations. Systematic searches of the PubMed, Embase, Web of Science, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and Chinese Biomedicine databases were undertaken to retrieve eligible studies. Odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were pooled to assess the strength of the association. In total, 8 case-control studies involving 1,293 cases and 2,647 controls were included in the meta-analysis. Overall, the results showed no evidence of significant association between the COMT rs4680 polymorphism and ovarian cancer risk in any of the assessed genetic models. Subgroup analyses by ethnicity also did not reveal any significant association in any genetic model (p>0.05). In conclusion, our findings suggest that the COMT rs4680 polymorphism may not contribute to the risk of ovarian cancer.

• Clinical and Experimental Pediatrics
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• 제52권1호
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• pp.87-92
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• 2009

목 적 : 가와사키병은 극동아시아인에서 다른 인종보다 높은 발생빈도를 보이고 여러 유전자 다형성이 보고되고 있다. COMT 는 염색체 22q11에 위치한 유전자로 메틸기접합을 촉진시켜 도파민, 에피네프린, 노르에피네프린 같은 카테콜아민 신경전달 물질을 불활성화 시키는 역할을 한다. COMT 유전자의 다형성은 estradiol 대사와 연관되어 혈압과 심근경색 등 심장질환과의 연관성이 보고되었고, 급성 관상동맥 질환과 관련이 있다고 보고되었다. 이 연구에서는 가와사키병에서 관상동맥 확장과 COMT 유전자 다형성과의 연관성을 알아보고자 하였다. 방 법 : 가와사키병 환자군 101명과 대조군 306명으로부터 혈액 2 mL를 채취하여 DNA를 분리하였으며, PCR 방법으로 COMT 유전자의 rs4680과 rs769224의 Guanine에서 Adenine으로의 단일염기다형성(SNP)을 분석하였다. 환자군 중 관상동맥의 확장을 동반한 37명과 관상동맥 확장이 없는 62명 대상으로 COMT 유전자의 단일염기다형성에 대한 관련성을 확인하였다. 결과 : 가와사키병 환자군과 대조군 사이에 COMT 유전자의 연관성은 보이지 않았다. COMT 유전자의 rs4680에서 가와사키병 환자군 중 관상동맥 확장을 가진 37명은 유전형 G/G (Val158 Val)는 19명(51.4%), G/A(Val158Met)는 13명(35.1%), A/A (Met158Met)는 5명(13.5%)이었고 관상동맥 확장이 없는 62명에서는 G/G (Val158Val)는 34명(54.8%), G/A (Val158Met)는 25명(40.3%), A/A (Met158Met)는 3명(4.8%)으로 통계학적 유의성이 없었으나(codominant P=0.32, dominant P=0.74, recessive P=0.13), rs769224에서는 관상동맥 확장을 가진 37명은 유전형 G/G는 30명(81.1%), G/A는 6명(16.2%), A/A는 1명(2.7 %)이었고 관상동맥 확장이 없는 62명에서는 G/G는 61명(98.4 %), G/A 1명(1.6%), A/A 0명(0.0%)으로 codominant와 dominant 모델에서 통계학적 유의성이 있었다(codominant P=0.0077, dominant P=0.0021, recessive P=0.16). 결론 : COMT 유전자의 단일염기다형성은 가와사키병과의 연관성은 보이지 않았고, rs4680 다형성과 관상동맥 확장은 연관성을 보이지 않았으나 rs769224 다형성과 관상동맥 확장은 통계학적으로 의미있게 연관성이 있었다.

• Archives of Pharmacal Research
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• 제20권5호
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• pp.465-470
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• 1997

The human cDNA clone UDPGTh2, encoding a liver UDP-glucuronosyltransferase (UDPGT), was isolated from a .gamma.gt 11 cDNA library by hybridization to mouse transferase cDNA clone, UDPGTm1. The two clones had 74% nlicleotide sequence identities in the coding region. UDPGTh2 encoded a 529 amino acid protein with an amino terminus membrane-insertion signal peptide and a carboxyl terminus membrane-spanning region. In order to establish substrate specificity, the clone was inserted into the pSVL vector (pUDPGTh2) and expressed in COS 1 cells. Sixty potential substrates were tested using cells transfected with pUDPGTh2. The order of relative substrate activity was as follows: 4-hydroxyestrone > estriol >2-hydroxyestriol > 4-hydroxyestradiol > $6{\alpha}$-hydroxyestradiol >$5{\alpha}$-androstane-$3{\alpha}$, $11{\beta}$, $17{\beta}$-triol=5${\beta}$-androstane-$3{\alpha}$ ${\beta}$, $17{\beta}$-triol. There were only trace amounts of gulcuronidation of 2-hydroxyestradiol and 2-hydroxyestrone, and in contrast to other cloned transferase, no gulcuronidation of either the primary estrogens and androgens (estrone, $17{\beta}$estradiol/testosterone, androsterone) or any of the exogenous substrates tested was detected. A lineweaver-Burk plot of the effect of 4-hydroxystrone concentration on the velocity of glucuronidation showed an apparent Km of $13{\mu}M$. The unique specificity of this transferase might play an important role in regulating the level and activity of these potent and active estrogen metabolites.

• 대한임상검사과학회지
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• 제54권4호
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• pp.316-324
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• 2022

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy in women of reproductive age. The genetics of PCOS is heterogeneous with the involvement of number of genes in the steroid synthesis pathway. The CYP11B2 encodes aldosterone synthase and the genetic variants might increase aldosterone secretion in PCOS cases. CYP1A1 is known to enhance the intraovarian catechol estrogen production and thus the propensity for PCOS. The present case-control study analyzed a total of 619 females for CYP11B2 (rs1799998) and CYP1A1 (rs4646903) polymorphisms. Obesity was examined according to body mass index (BMI) and waist hip ratio (WHR) categorization. Biochemical (lipid profile) analysis was performed in PCOS females. BMI (P=0.0001) and WHR (P=0.0001) revealed a statistically significant difference between PCOS cases and controls. The overall levels of triglycerides were higher in PCOS females. The genotype frequency distribution of CYP11B2 (rs1799998) polymorphism revealed statistically significant difference between PCOS cases and controls (P=0.017). However, CYP1A1 (rs4646903) polymorphism did not showed any association with PCOS. The present case-control association analysis is first from our region for CYP1A1 and CYP11B2 polymorphisms and is suggestive of genetic predisposition of steroidogenic genes among PCOS patients in the North-Indian Punjabi females.