In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds.

ABSTRACT: Cytochrome P450 46A1 (CYP46A1) is a central nervous system-specific enzyme, which catalyzes cholesterol 24-hydroxylation. Currently CYP46A1 is being evaluated in a clinical trial for activation by small doses of the anti-HIV drug efavirenz. Eight efavirenz-related compounds were investigated for CYP46A1 activation in vitro, induction of a CYP46A1 spectral response, spectral K_d values, interaction with the P450 allosteric sites, and a model of binding to the enzyme active site. We gained insight into structure-activity relationships of efavirenz for CYP46A1 activation and found that the investigated efavirenz primary metabolites are stronger and better activators of CYP46A1 than efavirenz. We also established that CYP46A1 is activated by racemates and that a conformational

SUBMITTER: Mast N 

PROVIDER: S-EPMC7226586 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature