Oxysterols are substrates for cholesterol sulfotransferase

被引:94
作者
Fuda, Hirotoshi
Javitt, Normal B.
Mitamura, Kuniko
Ikegawa, Shigeo
Strott, Charles A. [1 ]
机构
[1] NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA
[2] Kinki Univ, Fac Pharmaceut Sci, Osaka 5778502, Japan
关键词
steroid/sterol sulfotransferase; 7-ketocholesterol sulfate; cytotoxicity; HUMAN HYDROXYSTEROID SULFOTRANSFERASE; HUMAN ATHEROSCLEROTIC LESIONS; STEROL; 27-HYDROXYLASE; OXIDATION-PRODUCTS; BILE-ACID; HEPATIC-METABOLISM; ENDOTHELIAL-CELLS; LIPID-METABOLISM; 7-KETOCHOLESTEROL; EXPRESSION;
D O I
10.1194/jlr.M700018-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha/7 beta-hydroxycholesterol and 5 alpha,6 alpha/5 beta,6 beta-epoxycholesterol as well as the 7 alpha-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.
引用
收藏
页码:1343 / 1352
页数:10
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