title: Medical hypothesis: hyperhomocysteinemia is a risk factor for estrogen-induced hormonal cancer.
abstract: A novel mechanistic hypothesis is proposed which suggests that hyperhomocysteinemia is a risk factor for the development of estrogen-induced hormonal cancer in humans. Mechanistically, hyperhomocysteinemia may exert its pathogenic effects largely through metabolic accumulation of intracellular S-adenosyl-L-homocysteine, a strong non-competitive inhibitor of the catechol-O-methyltransferase-mediated methylation metabolism of endogenous and exogenous catechol estrogens (mainly 2-hydroxyestradiol and 4-hydroxyestradiol). While a strong inhibition of the methylation metabolism of 2-hydroxyestradiol would decrease the formation of 2-methoxyestradiol (an antitumorigenic endogenous metabolite of 17beta-estradiol), an inhibition of the methylation of 4-hydroxyestradiol would lead to accumulation of this hormonally-active and strongly procarcinogenic catechol estrogen metabolite. Both of these effects resulting from inhibition of the methylation metabolism of catechol estrogens would facilitate the development of estrogen-induced hormonal cancer in the target organs. This hypothesis also predicts that adequate dietary intake of folate, vitamin B6, and vitamin B12 may reduce hyperhomocysteinemia-associated risk for hormonal cancer. Experimental studies are warranted to determine the relations of hyperhomocysteinemia with the altered circulating or tissue levels of 4-hydroxyestradiol and 2-methoxyestradiol and also with the altered risk for estrogen-induced hormonal cancer.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. btzhu@cop.sc.edu
authors.forename: Bao Ting
authors.initials: BT
authors.lastname: Zhu
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000517:prevention & control; D002394:Catechol O-Methyltransferase / Q000502:physiology; D065098:Catechol O-Methyltransferase Inhibitors; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D004967:Estrogens / Q000633:toxicity; D002393:Estrogens, Catechol / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020138:Hyperhomocysteinemia / Q000453:epidemiology*; D007700:Kinetics; D008745:Methylation / Q000187:drug effects; D008954:Models, Biological; D009152:Mutagenicity Tests; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009376:Neoplasms, Hormone-Dependent / Q000453:epidemiology* / Q000517:prevention & control; D012307:Risk Factors; D012435:S-Adenosylhomocysteine / Q000009:adverse effects / Q000378:metabolism; D014594:Uterine Neoplasms / Q000453:epidemiology* / Q000517:prevention & control; D014805:Vitamin B 12 / Q000494:pharmacology / Q000627:therapeutic use; D025101:Vitamin B 6 / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016588:Anticarcinogenic Agents; D065098:Catechol O-Methyltransferase Inhibitors; D004967:Estrogens; D002393:Estrogens, Catechol; D004958:Estradiol; D025101:Vitamin B 6; D005492:Folic Acid; D012435:S-Adenosylhomocysteine; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D002394:Catechol O-Methyltransferase; D014805:Vitamin B 12