Metabolic Inactivation of Estrogens in Breast Tissue by UDP-glucuronosyltransferase Enzymes: an Overview

Overview

Journal Breast Cancer Res

Specialty Oncology

Date 2004 Nov 13

PMID 15535854

Citations 34

Authors

Chantal Guillemette

Alain Belanger

Johanie Lepine

Affiliations

Soon will be listed here.

Abstract

The breast tissue is the site of major metabolic conversions of estradiol (E2) mediated by specific cytochromes P450 hydroxylations and methylation by catechol-O-methytransferase. In addition to E2 itself, recent findings highlight the significance of 4-hydroxylated estrogen metabolites as chemical mediators and their link to breast cancer development and progression, whereas, in opposition, 2-methoxylated estrogens appear to be protective. Recent data also indicate that breast tissue possesses enzymatic machinery to inactivate and eliminate E2 and its oxidized and methoxylated metabolites through conjugation catalyzed by UDP-glucuronosyltransferases (UGTs), which involves the covalent addition of glucuronic acid. In opposition to other metabolic pathways of estrogen, the UGT-mediated process leads to the formation of glucuronides that are devoid of biologic activity and are readily excreted from the tissue into the circulation. This review addresses the most recent findings on the identification of UGT enzymes that are responsible for the glucuronidation of E2 and its metabolites, and evidence regarding their potential role in breast cancer.

Citing Articles

Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.

Mokhosoev I, Astakhov D, Terentiev A, Moldogazieva N Cells. 2024; 13(23).

PMID: 39682707 PMC: 11639897. DOI: 10.3390/cells13231958.

Validating Disease Associations of Drug-Metabolizing Enzymes through Genome-Wide Association Study Data Analysis.

Leskiw E, Whaley A, Hopwood P, Houston T, Murib N, Al-Falih D Genes (Basel). 2024; 15(10).

PMID: 39457450 PMC: 11507559. DOI: 10.3390/genes15101326.

Drug-drug interactions of plant alkaloids derived from herbal medicines on the phase II UGT enzymes: an introductory review.

Gunasaykaran S, Chear N, Ismail S, Mohammad N, Murugaiyah V, Ramanathan S Naunyn Schmiedebergs Arch Pharmacol. 2024; 398(2):1447-1464.

PMID: 39325152 DOI: 10.1007/s00210-024-03418-8.

X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma.

Hammouz R, Orzechowska M, Anusewicz D, Bednarek A Curr Oncol. 2023; 30(2):1395-1415.

PMID: 36826068 PMC: 9955992. DOI: 10.3390/curroncol30020107.

Distilling functional variations for human UGT2B4 upstream region based on selection signals and implications for phenotypes of Neanderthal and Denisovan.

Wang P, Yang Y, Shi X, Chen Y, Liu S, Wang H Sci Rep. 2023; 13(1):3134.

PMID: 36823244 PMC: 9950360. DOI: 10.1038/s41598-023-29682-x.

References

Adegoke O, Shu X, Gao Y, Cai Q, Breyer J, Smith J . Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) and risk of breast cancer. Breast Cancer Res Treat. 2004; 85(3):239-45. DOI: 10.1023/B:BREA.0000025419.26423.b8. View

Cecchin E, Russo A, Corona G, Campagnutta E, Martella L, Boiocchi M . UGT1A1*28 polymorphism in ovarian cancer patients. Oncol Rep. 2004; 12(2):457-62. View

Sparks R, Ulrich C, Bigler J, Tworoger S, Yasui Y, Rajan K . UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients. Breast Cancer Res. 2004; 6(5):R488-98. PMC: 549165. DOI: 10.1186/bcr818. View

Lepine J, Bernard O, Plante M, Tetu B, Pelletier G, Labrie F . Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab. 2004; 89(10):5222-32. DOI: 10.1210/jc.2004-0331. View

Brooks S, Horn L . Hepatic sulfation of estrogen metabolites. Biochim Biophys Acta. 1971; 231(1):233-41. DOI: 10.1016/0005-2760(71)90272-4. View

Guldberg H, Marsden C . Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev. 1975; 27(2):135-206. View

Vermeulen A . The hormonal activity of the postmenopausal ovary. J Clin Endocrinol Metab. 1976; 42(2):247-53. DOI: 10.1210/jcem-42-2-247. View

Hobkirk R . Steroid sulfotransferases and steroid sulfate sulfatases: characteristics and biological roles. Can J Biochem Cell Biol. 1985; 63(11):1127-44. DOI: 10.1139/o85-141. View

Longcope C, Gorbach S, Goldin B, Woods M, Dwyer J, Warram J . The metabolism of estradiol; oral compared to intravenous administration. J Steroid Biochem. 1985; 23(6A):1065-70. DOI: 10.1016/0022-4731(85)90068-8. View

10.

Cauley J, Gutai J, Sandler R, LaPorte R, Kuller L, SASHIN D . The relationship of endogenous estrogen to bone density and bone area in normal postmenopausal women. Am J Epidemiol. 1986; 124(5):752-61. DOI: 10.1093/oxfordjournals.aje.a114451. View

11.

Thijssen J, Blankenstein M . Endogenous oestrogens and androgens in normal and malignant endometrial and mammary tissues. Eur J Cancer Clin Oncol. 1989; 25(12):1953-9. DOI: 10.1016/0277-5379(89)90377-5. View

12.

Belanger A, Caron S, Labrie F, Naldoni C, Dogliotti L, Angeli A . Levels of eighteen non-conjugated and conjugated steroids in human breast cyst fluid: relationships with cyst type. Eur J Cancer. 1990; 26(3):277-81. DOI: 10.1016/0277-5379(90)90222-f. View

13.

Lazard D, Zupko K, Poria Y, Nef P, Lazarovits J, Horn S . Odorant signal termination by olfactory UDP glucuronosyl transferase. Nature. 1991; 349(6312):790-3. DOI: 10.1038/349790a0. View

14.

Labrie F . Intracrinology. Mol Cell Endocrinol. 1991; 78(3):C113-8. DOI: 10.1016/0303-7207(91)90116-a. View

15.

Ritter J, Chen F, Sheen Y, Tran H, Kimura S, Yeatman M . A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem. 1992; 267(5):3257-61. View

16.

Albin N, Massaad L, Toussaint C, Mathieu M, Morizet J, Parise O . Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. Cancer Res. 1993; 53(15):3541-6. View

17.

Fotsis T, Zhang Y, Pepper M, Adlercreutz H, Montesano R, Nawroth P . The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature. 1994; 368(6468):237-9. DOI: 10.1038/368237a0. View

18.

DAmato R, Lin C, Flynn E, Folkman J, Hamel E . 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci U S A. 1994; 91(9):3964-8. PMC: 43703. DOI: 10.1073/pnas.91.9.3964. View

19.

Senafi S, Clarke D, Burchell B . Investigation of the substrate specificity of a cloned expressed human bilirubin UDP-glucuronosyltransferase: UDP-sugar specificity and involvement in steroid and xenobiotic glucuronidation. Biochem J. 1994; 303 ( Pt 1):233-40. PMC: 1137581. DOI: 10.1042/bj3030233. View

20.

Monaghan G, Clarke D, Povey S, See C, Boxer M, Burchell B . Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4q13. Genomics. 1994; 23(2):496-9. DOI: 10.1006/geno.1994.1531. View