Oxysterols are substrates for cholesterol sulfotransferase.
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 7alpha/7beta-hydroxycholesterol and 5alpha,6alpha/5beta,6beta-epoxycholesterol as well as the 7alpha-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.
Fuda
Hirotoshi
H
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, USA.
Javitt
Normal B
NB
Mitamura
Kuniko
K
Ikegawa
Shigeo
S
Strott
Charles A
CA
D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007653:Ketocholesterols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D007653:Ketocholesterols; D011993:Recombinant Fusion Proteins; D013256:Steroids; D002784:Cholesterol; D015238:Sulfotransferases; C043456:cholesterol sulfotransferase