Screening for Drug-induced Effects on Cholesterol Metabolism

Cytochrome P450 46A1 (CYP46A1) is predominantly expressed in the brain and catalyses the conversion of cholesterol to 24-hydroxy cholesterol. As this pathway influences brain function, modulation of CYP46A1 activity has been implicated in the pathogenesis and/or progression of certain neurodegenerative disorders. Therefore, assessing the impact of new chemical entities on the inhibition or activation of CYP46A1 will afford a better understanding of the potential safety or therapeutic implications.

Cyprotex recently presented a poster at the 2022 AAPS PharmSci 360 conference in Boston, MA. The research covered the development and validation of a high throughput screening platform for characterisation of inhibitors and activators of CYP46A1 from a compound library of 2321 FDA approved drugs. Due to shorter LC-MS/MS run times, the reliability of testosterone as a replacement substrate for cholesterol was assessed. For both substrates, enzyme kinetics studies were performed to establish suitable incubation conditions. Known CYP46A1 inhibitors were assessed in the assay and compared against literature values.

Initial compound library screening was performed using cassettes of 4 compounds per well and testosterone as substrate. Follow-up screening of individual compounds was performed using both testosterone and cholesterol as substrates which identified 12 common activators and 15 common inhibitors of CYP46A1.

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