Oxysterols are substrates for cholesterol sulfotransferase

Abstract

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 7a/ 7b-hydroxycholesterol and 5a,6a/5b,6b-epoxycholesterol as well as the 7a-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, H., N. B. Javitt, K. Mitamura, S. Ikegawa, and C. A. Strott. Oxysterols are substrates for cholesterol sulfotransferase. J. Lipid Res.

Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands

“…α-CE is the only epimer of CE found in the adrenal cortex, where it is produced by an as-yet-unidentified cytochrome p450 (35). α-CE can be esterified by Sult2B1b (36) to give a 3β-sulfated product that antagonizes liver X-receptor sig- naling (37,38), or it can be transformed by glutathione transferase into 3β,5α-dihydroxycholestan-6β-yl-S-glutathione (39,40). In addition, we have reported that the aminolysis of α-CE by biogenic amines under catalytic conditions is possible and generates powerful cell-differentiating alkylaminooxysterols (30).…”

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

“…Another potential detoxifi cation pathway that has been proposed for 7KCh is sulfation ( 7,86 ). One study demonstrated that transfected 293T cells overexpressing SULT2B1b could form 7-ketocholesterol-3-sulfate (7KChS) when incubated with 7KCh ( 86 ). Cells overexpressing SULT2B1b showed a slight resistance to 7KCh-medited toxicity ( 86 ).…”

Is Endothelial Nitric Oxide Synthase a Moonlighting Protein Whose Day Job is Cholesterol Sulfate Synthesis? Implications for Cholesterol Transport, Diabetes and Cardiovascular Disease

“…Caveolin is therefore well positioned to bring cholesterol (whether retrieved from serum HDL or internally synthesized) into close proximity to sulfate synthesized by eNOS. The attachment of sulfate to cholesterol via the sulfotransferase SULT2B1b [75] requires an activation step which consumes ATP to produce 3'-phosphoadenosine-5'-phosphosulfate (PAPS). As discussed later, ATP can be provided by glycolysis.…”