Oxysterols are substrates for cholesterol sulfotransferase

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Endocrinology

Background:

• Oxysterols, cholesterol derivatives, have diverse biological effects, including cytotoxicity.
• The role of oxysterols in retinal macular degeneration and atheromatous lesions is significant, yet their metabolic fate remains unclear.
• 7-ketocholesterol (7-KC) is a key oxysterol implicated in disease pathogenesis.

Purpose of the Study:

• To investigate the metabolic fate of oxysterols, specifically 7-ketocholesterol (7-KC).
• To determine if steroid/sterol sulfotransferase SULT2B1b can metabolize oxysterols.
• To assess the potential of SULT2B1b in mitigating oxysterol-induced cytotoxicity.

Main Methods:

• Transfection of 293T cells with SULT2B1b cDNA to assess its effect on 7-KC cytotoxicity.
• Quantification of SULT2B1b protein synthesis and 7-KC sulfoconjugate (7-KCS) production.
• Assessment of cell viability in response to 7-KC and 7-KCS.
• Testing the resistance of MCF-7 cells (high SULT2B1b expression) to 7-KC.
• Evaluating SULT2B1b activity against a range of oxysterol substrates.

Main Results:

• Steroid/sterol sulfotransferase SULT2B1b efficiently sulfonates various oxysterols, including 7-KC, forming 7-KC sulfoconjugate (7-KCS).
• Transfection with SULT2B1b attenuated the cytotoxic effects of 7-KC on 293T cells, correlating with 7-KCS production.
• Exogenous 7-KCS did not induce cell death, indicating its reduced toxicity.
• MCF-7 cells, expressing high levels of SULT2B1b, exhibited significant resistance to 7-KC.
• SULT2B1b demonstrated sulfonation activity against multiple oxysterols, including hydroxycholesterols and epoxycholesterols.

Conclusions:

• SULT2B1b effectively metabolizes a variety of potentially harmful oxysterols through sulfonation.
• Sulfonation by SULT2B1b converts cytotoxic oxysterols into less harmful sulfoconjugates.
• SULT2B1b represents a significant metabolic pathway for detoxifying oxysterols, offering a potential mechanism to mitigate oxysterol-induced pathologies in vivo.