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Journal of Lipid Research, Vol. 48, 1343-1352, June 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Oxysterols are substrates for cholesterol sulfotransferase

Hirotoshi Fuda^*, Normal B. Javitt^1,*, Kuniko Mitamura, Shigeo Ikegawa and Charles A. Strott^2,*

^* Section on Steroid Regulation, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510
Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan

Published, JLR Papers in Press, March 8, 2007.

¹ Present address of N. B. Javitt: New York University Medical Center, 550 First Avenue, New York, NY 10016.

² To whom correspondence should be addressed. e-mail: chastro{at}mail.nih.gov

Oxysterols constitute a class of cholesterol derivatives that exhibit broad biological effects ranging from cytotoxicity to regulation of nuclear receptors. The role of oxysterols such as 7-ketocholesterol (7-KC) in the development of retinal macular degeneration and atheromatous lesions is of particular interest, but little is known of their metabolic fate. We establish that the steroid/sterol sulfotransferase SULT2B1b, known to efficiently sulfonate cholesterol, also effectively sulfonates a variety of oxysterols, including 7-KC. The cytotoxic effect of 7-KC on 293T cells was attenuated when these cells, which do not express SULT2B1b, were transfected with SULT2B1b cDNA. Importantly, protection from 7-KC-induced loss of cell viability with transfection correlated with the synthesis of SULT2B1b protein and the production of the 7-KC sulfoconjugate (7-KCS). Moreover, when 7-KCS was added to the culture medium of 293T cells in amounts equimolar to 7-KC, no loss of cell viability occurred. Additionally, MCF-7 cells, which highly express SULT2B1b, were significantly more resistant to the cytotoxic effect of 7-KC. We extended the range of oxysterol substrates for SULT2B1b to include 7/7ß-hydroxycholesterol and 5,6/5ß,6ß-epoxycholesterol as well as the 7-hydroperoxide derivative of cholesterol. Thus, SULT2B1b, by acting on a variety of oxysterols, offers a potential pathway for modulating in vivo the injurious effects of these compounds.

Supplementary key words steroid/sterol sulfotransferase • 7-ketocholesterol sulfate • cytotoxicity

Abbreviations: BCD, 2-hydroxypropyl-ß-cyclodextrin; CCK-8, Cell Counting Kit-8; ESI, electrospray ionization; 7-KC, 7-ketocholesterol; 7-KCS, 7-ketocholesterol sulfate; PAPS, 3'-phosphoadenosine 5'-phosphosulfate

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