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Journal of Biochemistry 2005 137(3):401-406; doi:10.1093/jb/mvi047
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© 2005 The Japanese Biochemical Society

Regular Paper

Oral Contraceptives as Substrates and Inhibitors for Human Cytosolic SULTs

Shin Yasuda, Masahito Suiko and Ming-Cheh Liu*

Biomedical Research Center, The University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708, USA

* To whom correspondence should be addressed. Tel: +1-903-877-2862, Fax: +1-903-877-2863, E-mail: ming.liu{at}uthct.edu

ABSTRACT

Cytosolic sulfotransferases (SULTs) in mammals are involved in the biotransformation and homeostasis of various endogenous and xenobiotic compounds. The current study aimed to examine the sulfation of contraceptive compounds by various human cytosolic SULTs and to investigate the inhibitory effects and mode of action of these compounds on the sulfation of 17ß-estradiol, a major endogenous estrogen. A systematic study using all eleven known human cytosolic SULTs revealed the differential substrate specificity of these enzymes for the eight representative contraceptive compounds and two endogenous estrogens (estrone and 17ß-estradiol) tested as substrates. Activity data showed that SULT1A1 displayed the strongest activity toward 17{alpha}-ethynylestradiol. Kinetic studies revealed that the V max value of the sulfation of 17{alpha}-ethynylestradiol by SULT1A1 was 1.64 times that of the sulfation of 17ß-estradiol, while the K m values were almost equal for the two compounds. The inhibitory effects of three contraceptive compounds on the sulfation of 17ß-estradiol by SULT1A1 were examined. IC50 values determined were 0.193, 1.84, and 2.98 mM, respectively, for 19-norethindrone acetate, ethynodiol diacetate and mifepristone. Kinetic analyses indicated that the mechanism underlying the inhibition by these contraceptives is of a mixed noncompetitive type. Metabolic labeling experiments confirmed the sulfation of contraceptive compounds and the release of their sulfated derivatives by HepG2 human hepatoma cells. Collectively, the results obtained suggest a role of sulfation in the metabolism of contraceptive compounds in vivo. Moreover, in view of their inhibitory effects on the sulfation of 17ß-estradiol, these compounds may potentially act to disrupt the homeostasis of endogenous estrogens.


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