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

Mast N, Verwilst P, Wilkey CJ, Guengerich FP, Pikuleva IA
J Med Chem. 2020 63 (12): 6477-6488

PMID: 31617715 · PMCID: PMC7226586 · DOI:10.1021/acs.jmedchem.9b01383

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 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-selection mechanism is operative in CYP46A1. The results suggest structural modifications of efavirenz to further increase CYP46A1 activation without inhibition at high compound concentrations. It is possible that not only efavirenz but its metabolites activate CYP46A1 in vivo.

MeSH Terms (13)

Alkynes Allosteric Site Benzoxazines Catalytic Domain Cholesterol Cholesterol 24-Hydroxylase Cyclopropanes Cytochrome P-450 CYP3A Inducers Humans Hydroxylation In Vitro Techniques Pharmaceutical Preparations Protein Conformation

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