Interactions of galeterone and its 3‐keto‐Δ4 metabolite (D4G) with one of the key enzymes of corticosteroid biosynthesis – steroid 21‐monooxygenase (CYP21A2).

Masamrekh, Rami A.; Filippova, Tatiana A.; Sherbakov, Kirill A.; Veselovsky, Alexander V.; Shumyantseva, Victoria V.; Kuzikov, Alexey V.

We have investigated interactions of galeterone and its pharmacologically active metabolite – 3‐keto‐Δ4‐galeterone (D4G) – with one of the key enzymes of corticosteroid biosynthesis – steroid 21‐monooxygenase (CYP21A2). It was shown by absorption spectroscopy that both compounds induce type I spectral changes of CYP21A2. Spectral dissociation constants (KS) of complexes of CYP21A2 with galeterone or D4G were calculated as 3.1 ± 0.7 μm and 4.6 ± 0.4 μm, respectively. It was predicted by molecular docking that both ligands similarly bind to the active site of CYP21A2. We have revealed using reconstituted monooxygenase system that galeterone is a competitive inhibitor of CYP21A2 with the inhibition constant (Ki) value of 12 ± 3 μm, while D4G at the concentrations of 10 and 25 μm does not inhibit the enzyme. Summarizing, based on the in vitro analyses we detected inhibition of CYP21A2 by galeterone and lack of the influence of D4G on this enzyme.

BIOSYNTHESIS; CORTICOSTEROIDS; ENZYMES; MOLECULAR docking; STEROIDS; SULFATASES

Fundamental & Clinical Pharmacology, 2021, Vol 35, Issue 2, p423

0767-3981

Academic Journal

10.1111/fcp.12607