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Drugs and Scaffold that Inhibit Cytochrome P450 27A1 (CYP27A1) in Vitro and in Vivo.

Drugs and Scaffold that Inhibit Cytochrome P450 27A1 (CYP27A1) in Vitro and in Vivo.
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Lam M, Mast N, Pikuleva I,


Lam M, Mast N, Pikuleva I, (click to view)

Lam M, Mast N, Pikuleva I,

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Molecular pharmacology 2017 11 30() pii mol.117.110742
Abstract

Cytochrome P450 27A1 (CYP27A1) is a ubiquitous enzyme that hydroxylates cholesterol and other sterols. Complete CYP27A1 deficiency due to genetic mutations is detrimental to human health, whereas 50% of activity retention is not and does not affect the whole body cholesterol levels. CYP27A1 is considered as a potential therapeutic target in breast cancer and age-related neurodegenerative diseases; however CYP27A1 inhibition should be 50%. Herein, 131 pharmaceuticals were tested for their effect on CYP27A1-mediated cholesterol 27-hydroxylation by in vitro enzyme assay. Of them, 14 drugs inhibited CYP27A1 by 75% and were evaluated for in vitro binding to the enzyme active site and inhibition constants. All drugs except one (dasatanib) elicited a spectral response in CYP27A1 and had Ki values for cholesterol 27-hydroxylation either in the submicromolar (clevidipine, delaviridne, etravirine, felodipine, nicardipine, nilotinib, and sorafenib) or low micromolar range (abiratone, candesartan, celecoxib, dasatanib, nilvadipine, nimodipine, and regorafenib). Clevidipine, felodipine, nicardipine, nilvadipine, and nimodipine have the same 1,4-dihydropyridine scaffold and are indicated for hypertension. We used two of these antihypertensives (felodipine and nilvadipine) for administration to mice at a 1 mg/kg of body weight dose, daily, for 7 days. Mouse 27-hydroxycholesterol levels in the plasma, brain, and liver were reduced, whereas tissue levels of total cholesterol were unchanged. Structure-activity relationships within the 1,4-dihydropyridine scaffold were investigated, and features important for CY27A1 inhibition were identified. We confirmed our previous finding that CYP27A1 is a druggable enzyme and found additional drugs as well as the scaffold with potential for partial CYP27A1 inhibition in humans.

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