Chapter 6: Estrogen Metabolism by Conjugation

Raftogianis, Rebecca B.; Creveling, Cyrus R.; Weinshilboum, Richard; Weisz, Judith

doi:10.1093/oxfordjournals.jncimonographs.a024234

Cited by 264 publications

(230 citation statements)

References 73 publications

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“…Given that individual CE-metabolizing genes participate cooperatively in CE metabolism 11 and that an increased risk of cancer due to a combined effect of genes belonging to a common antitumor pathway has been demonstrated in a mouse model, 36 we examined whether a joint effect of these CE-metabolizing genes was associated with breast cancer development by determining the breast cancer risk associated with harboring different numbers of putative high-risk genotypes (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…(iii) A joint contribution of individual CE-metabolizing genes to increased breast cancer risk was explored in several ways, based on known CE metabolic mechanisms. 11 Using a dummy variable coding scheme, 30 we estimated breast cancer risk (aOR) in women harboring different numbers of putative high-risk genotypes. The strength of this approach is that it is more mechanistically reasonable at the cellular level, because it is not dependent on the assumption that the difference in risk between women with the same difference in the number of high-risk genotypes will be the same, irrespective of the actual number of high-risk genotypes.…”

Section: Discussionmentioning

confidence: 99%

“…The genes examined were catechol-O-methyltransferase (COMT), sulfotransferase 1A1 (SULT1A1), and UDP-glucuronosyltransferase 1A1 (UGT1A1), involved in CE detoxification by, respectively, methylation, sulfation, or glucuronidation, manganese superoxide dismutase (MnSOD), involved in protection against ROS-mediated oxidation, and GSTM1 and GSTT1, 2 of the glutathione S-transferase (GST) superfamily, involved in CE-Q inactivation. 11 Our aims were to determine whether genotypic polymorphism in these genes was associated with an increased risk of breast cancer, and whether the association between genotypes and risk was modified by estrogen exposure. Finally, because the genotypic polymorphism of the genes involved in DNA double-strand break repair (DSBR) has already been defined in the cases and controls used in our present study, 12,13 we had the unique opportunity of using this information to explore a possible interaction between CE metabolism and DSBR.…”

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Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Cheng

Chen

Huang

et al. 2004

Intl Journal of Cancer

102

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Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CEsemiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (>26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (>12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.Key words: breast cancer; estrogen; catechol estrogen; polymorphism; molecular epidemiology An increased risk of breast cancer due to prolonged exposure to estrogen has been well documented by epidemiological observations showing that estrogen-related risk factors, including age at menarche, age at menopause, parity and age at first full-term pregnancy (FFTP), are significantly associated with breast cancer risk. 1,2 Why estrogen exposure should increase breast cancer risk is an intriguing question that has not been conclusively answered. One simple explanation is that the proliferative effect of estrogen on breast epithelium promotes the growth of tumor cells, leading to progression of breast cancer. [3...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Cheng

Chen

Huang

et al. 2004

Intl Journal of Cancer

102

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“…Sulfated steroid hormones are widely believed to serve an important biological role as steroid hormone precursors or reservoirs for steroid hormone-responsive tissues. 43 Liver is proposed to be a major site of steroid sulfation. ES, produced by the liver cytosolic sulfotransferase, is secreted not only into the bile but also into the systemic circulation.…”

Section: Discussionmentioning

confidence: 99%

Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate

et al. 2007

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The liver plays an important role in the elimination of endogenous and exogenous lipophilic organic compounds from the body, which is mediated by various carrier proteins that differ in substrate specificity and kinetic properties. Here, we have characterized a novel member of the organic anion transporter family (SLC22) isolated from human liver. The transporter named organic anion transporter 7 (OAT7/ SLC22A9) showed 35% to 46% identities to those of other organic anion transporters of SLC22 family. When expressed in Xenopus oocytes, OAT7 mediated Na ؉ -independent, highaffinity transport of sulfate-conjugated steroids, estrone sulfate (ES; K m ‫؍‬ 8.7 M), and dehydroepiandrosterone sulfate (K m ‫؍‬ 2.2 M). In addition, OAT7 interacted with negatively charged sulfobromophthalein, indocyanine green, and several sulfate-conjugated xenobiotics. In contrast, glucuronide and glutathione conjugates exhibited no inhibitory effects on OAT7-mediated

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“…7,8 A need for additional mechanism(s) for the inactivation of 4-OH-CEs, in particular in tissues in which both 2-and 4-OH-CEs are generated, is indicated by the observation that 2-OH-CEs inhibit the O-methylation of 4-OH-CEs. 9 We reasoned that in such tissues glucuronidation could provide the additional protection needed.…”

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confidence: 99%

Expression of UGT2B7, a UDP-Glucuronosyltransferase Implicated in the Metabolism of 4-Hydroxyestrone and All-Trans Retinoic Acid, in Normal Human Breast Parenchyma and in Invasive and in Situ Breast Cancers

Gestl¹,

Green²,

Shearer³

et al. 2002

The American Journal of Pathology

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Glucuronidation, mediated by UDP-glucuronosyltransferases (UGTs), affects the actions and disposition of diverse endo-and xenobiotics. In the case of catecholestrogens (CEs), glucuronidation is likely to block their oxidation to quinone estrogens that are the putative mediators of CEs' actions as initiators of cancers. The goal of this study was to determine whether UGT2B7, the isoenzyme with a high affinity for 4-hydroxyestrone, is expressed in human breast parenchyma. Glucuronidation of 4-hydroxyestrone has relevance to breast carcinogenesis because quinone metabolites of 4-hydroxylated CEs can form potentially mutagenic depurinating DNA adducts, and because in breast tissue estrone is likely to be the predominant estrogen available for 4-hydroxylation. Using reverse transcriptase-polymerase chain reaction, immunocytochemistry, immunoblot analyses, and assays of glucuronidation of 4-hydroxyestrone, we show that UGT2B7 is expressed in human mammary epithelium, and that its expression is dramatically reduced in invasive breast cancers. In many in situ carcinomas, however, 4-hydroxyestrone immunostaining was not only preserved but even more intense than in normal mammary epithelium. The finding of reduced UGT2B7 protein and glucuronidation of 4-hydroxyestrone in invasive cancers suggests a tumor-suppressor function for the enzyme. Recent identification of all-trans retinoic acid as a substrate of UGT2B7 suggests that this function includes the generation of retinoyl-␤-glucuronide, a potent mediator of actions of retinoids important for maintaining epithelia in a differentiated state. Current knowledge does not provide any ready explanation for the apparent increase in UGT2B7 expression in carcinomas in situ. However, this finding, together with reduced immunostaining at loci showing breach of the basement membrane (microinvasion), suggests involvement of UGT2B7-catalyzed reaction(s) in protection against invasion of surrounding tissue by cancer cells.

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Chapter 6: Estrogen Metabolism by Conjugation

Cited by 264 publications

References 73 publications

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate

Expression of UGT2B7, a UDP-Glucuronosyltransferase Implicated in the Metabolism of 4-Hydroxyestrone and All-Trans Retinoic Acid, in Normal Human Breast Parenchyma and in Invasive and in Situ Breast Cancers

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