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Estrogen Metabolism

OMIM numbers: 116790 (COMT), 108330 (CYP1A1), 171150 (SULT1A1)

Dipl.-Biol. Birgit Busse

Scientific Background

Degradation of estrogen is facilitated by various enzyme systems, such as the enzymes CYP1A1, COMT and SULT1A1. CYP1A1 converts estrogen to catechol estrogen, the sulfation of estrogens (toxification) and catechol estrogens (detoxification) is facilitated by SULT1A1. COMT facilitates methylation of the catechol estrogens (detoxification). Due to the associations between the estrogen metabolism and the enzymes involved in the metabolism, the association between single gene variants and the risk for breast cancer both with and without hormone replacement therapy is discussed controversially in the literature. 

CYP1A1: Cytochrom P450-1A1 (CYP1A1) belongs to the group of the phase I enzymes and is, among other things, facilitating the degradation of estradiol to the catechol estrogen 2-hydroxyestradiol by hydroxylation. Two frequently occurring polymorphisms in the CYP1A1 gene (T3801C and A2455G) lead to an increased enzyme activity, resulting in accelerated formation of metabolites such as catechol estrogen, which are thought to be cancerogenic. Yet, an association between the CYP1A1 variants and an increased breast cancer risk could not be confirmed in both a meta analysis of 17 studies (Justenhoven et al, Breast Can Res Treat epub, 2007) as well as other studies (Masson et al, Am J Epidem 161:901, 2005, Cheng et al, J Hum Genet 52:423, 2007). Moreover, a study of Rebbeck (et al, Can Epid Biom Prev 16:1318, 2007) shows no association between the CYP1A1 variants and an increased breast cancer risk under hormone replacement therapy.

COMT: As a phase II enzyme, catechol-O-methyltransferase (COMT) catalyzes the transfer of methyl groups to endogenous and exogenous catechols and is therefore part of their inactivation. Catechol estrogenes are formed by hydroxylation of estrogenes and are thought to contribute to estrogen induced tumorgenesis. A variant in the codon 108/158 of the COMT gene, through which the amino acid valine is substituted with methionine (COMT-V108/158M) has been associated with a low activity of the enzyme (low activity allele). The result is a slowed catechol metabolism. An association between the COMT variant and an increased breast cancer risk could not be confirmed in both a meta analysis of 17 studies (Justenhoven et al, Breast Can Res Treat epub, 2007) as well as other studies (Masson et al, Am J Epidem 161:901, 2005, Cheng et al, J Hum Genet 52:423, 2007).Rebbeck et al, Can Epid Biom Prev 16:1318 2007; Cussenot et al, J Clin Onc 25:3596, 2007).

SULT1A1: Sulfotransferase 1A1 (SULT1A1) is a phase II enzyme and belongs to the group of phenolic sulfotransferases, which are involved in the metabolism of various endogenous and exogenous substances. Both estrogen and its metabolite catechol estrogen are substrates of SULT1A1. The result of sulfation of estrogen is the toxic intermediate metabolite estrogen sulfate; whereas sulfation of catechol estrogen is a detoxification process. A polymorphism in exon 7 (SULT1A1*2 Arg213His) leads to an enzyme with reduced activity and a slower substrate conversion. This has two consequences for the estrogen metabolism: on the one hand, if a low activity allele is present, less toxic estrogen sulfate is being formed but on the other hand, detoxification of catechol estrogen is limited in this degradation pathway. Therefore, the significance of the SULT1A1 variant Arg213His is discussed controversially. However studies suggest that the SULT1A1-R213H polymorphism seems to have no influence on breast cancer susceptibility (Rebbeck et al, Can Epid Biom Prev 16:1318 2007).