Cholesterol epoxide is a direct-acting mutagen.

Area of Science:

• Biochemistry
• Toxicology
• Genetics

Background:

• Cholesterol oxidation produces various metabolites, including cholesterol epoxides.
• The mutagenic and cytotoxic potential of these metabolites requires investigation.

Purpose of the Study:

• To evaluate the mutagenicity and cytotoxicity of cholesterol 5 alpha, 6 alpha-epoxide.
• To investigate the role of its metabolite, cholestane-3 beta, 5 alpha, 6 beta-triol, in cellular toxicity and DNA synthesis inhibition.

Main Methods:

• Treatment of V79 Chinese hamster lung fibroblasts with cholesterol epoxide.
• Measurement of 8-azaguanine-resistant mutant frequencies.
• Assessment of cellular accumulation and metabolic transformation of cholesterol epoxide.
• Evaluation of cytotoxicity and DNA synthesis inhibition by cholesterol epoxide and its triol metabolite.

Main Results:

• Cholesterol epoxide treatment increased mutant frequencies 4.6- to 11.8-fold compared to spontaneous rates.
• Cholesterol epoxide is a weak direct-acting mutagen that accumulates in cells.
• The metabolite cholestane triol is more toxic and inhibits DNA synthesis more potently than the epoxide.
• At concentrations below 17.8 microM, cholestane triol was not significantly mutagenic.
• Low epoxide hydrolase activity favored mutagenicity, while rapid conversion to cholestane triol favored cytotoxicity.

Conclusions:

• Cholesterol epoxide exhibits mutagenic properties, but its conversion to cholestane triol can mitigate this effect.
• The balance between cholesterol epoxide conversion to cholestane triol and epoxide hydrolase activity influences cellular outcomes, with rapid conversion leading to cytotoxicity and low conversion favoring mutagenicity.