Catecholestrogen sulfation: possible role in carcinogenesis.
A growing body of evidence supports the hypothesis that estrogens can be carcinogens as a result of their conversion to genotoxins after biotransformation to form the catecholestrogens (CEs) 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2). CEs can then undergo further metabolism to form quinones that interact with DNA to form either stable or depurinating adducts. These events could potentially be interrupted by the sulfate conjugation of both the parent estrogens and/or the CEs. We set out to determine whether CEs can serve as substrates for sulfate conjugation, and-if so-which of the growing family of human sulfotransferase (SULT) isoforms are capable of catalyzing those reactions. We determined apparent K(m) values for 10 recombinant human SULT isoforms, as well as the three most common allozymes for SULT1A1 and SULT1A2, with 2-OHE1, 2-OHE2, 4-OHE1, and 4-OHE2, and with the endogenous estrogens, estrone (E1) and 17beta-estradiol (E2), as substrates. With the exception of SULT1B1, SULT1C1, and SULT4A1, all of the human SULTs studied catalyzed the sulfate conjugation of CEs. SULT1E1 had the lowest apparent K(m) values, 0.31, 0.18, 0.27, and 0.22 microM for 4-OHE1, 4-OHE2, 2-OHE1, and 2-OHE2, respectively. These results demonstrate that SULTs can catalyze the sulfate conjugation of CEs, and they raise the possibility that individual variation in this pathway for estrogen and CE metabolism as a result of common genetic polymorphisms could represent a risk factor for estrogen-dependent carcinogenesis.
Adjei
Araba A
AA
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School-Mayo Clinic-Mayo Foundation, Rochester, Minnesota 55905, USA.
Weinshilboum
Richard M
RM
D002273:Carcinogens / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D002393:Estrogens, Catechol / Q000378:metabolism*; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology; D012307:Risk Factors; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism*
D002273:Carcinogens; D002393:Estrogens, Catechol; D006894:Hydroxyestrones; D007527:Isoenzymes; D013431:Sulfates; D004958:Estradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D015238:Sulfotransferases