Abstract
Human cytosolic sulfotransferases (SULTs) catalyze the sulfate conjugation of several important endo- and xenobiotics. Among the superfamily of SULT enzymes, SULT1A1 catalyzes the sulfation of small planar phenolic compounds, whereas SULT1E1 has a major role in estrogen conjugation. The human SULT1A1 gene has common single nucleotide polymorphisms that define three allozymes, SULT1A1*1, *2, and *3. The enzyme kinetics of SULT1A1 allozymes and SULT1E1 were characterized for the polyphenolic substrates apigenin, chrysin, epicatechin, quercetin, and resveratrol. Purified recombinant SULT proteins were generated in a baculoviral-insect cell system, and incubated in vitro with each substrate to determine catalytic activity. The effect of polyphenol sulfation was examined in mammalian cell lines stably expressing SULT1E1. For all polyphenols investigated, “normal-activity” SULT1A1*1 allozyme had significantly greater Vmax estimates than SULT1E1, and allele-specific differences in SULT1A1-mediated sulfation were observed. The polymorphic SULT1A1*2 allozyme exhibited low activity toward apigenin, epicatechin, and resveratrol. SULT1A1*1 and *3 acted as normal-activity allozymes for these substrates. Altered cellular proliferation was observed in MCF-7 cells stably expressing SULT1E1 upon treatment with chrysin, quercetin, or resveratrol, thus suggesting inactivation of these compounds by SULT1E1. These results suggest an important role for SULT isozymes and their pharmacogenetics in polyphenol disposition.
Footnotes
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This work was partially supported by grants from the Cancer Research and Prevention Foundation, Alexandria VA, and Temple University Research Incentive Funds (to S.N.).
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This work was presented as poster presentations at the 14th North American ISSX Meeting, 2006 Oct 22–26; Rio Grande, Puerto Rico; International Society for the Study of Xenobiotics, Washington, DC (Ung and Nagar, 2006a); and the 2006 AAPS Annual Meeting and Exposition, 2006; 2006 Oct 28–Nov 3; San Antonio TX; American Association of Pharmaceutical Scientists, Arlington, VA (Ung and Nagar, 2006b).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.013987.
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ABBREVIATIONS: SULT, sulfotransferase; UGT, uridine diphosphoglucuronosyltransferase; PAPS, 3′-phosphoadenosine 5′-phosphosulfate, DMSO, dimethyl sulfoxide.
- Received November 17, 2006.
- Accepted February 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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