Identification of New Substrates and Inhibitors of Human CYP2A7.

Autor: Ashraf RA; School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China., Liu S; Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Free University Berlin, 14195 Berlin, Germany., Wolf CA; Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Free University Berlin, 14195 Berlin, Germany., Wolber G; Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Free University Berlin, 14195 Berlin, Germany., Bureik M; School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2024 May 08; Vol. 29 (10). Date of Electronic Publication: 2024 May 08.
DOI: 10.3390/molecules29102191
Abstrakt: CYP2A7 is one of the most understudied human cytochrome P450 enzymes and its contributions to either drug metabolism or endogenous biosynthesis pathways are not understood, as its only known enzymatic activities are the conversions of two proluciferin probe substrates. In addition, the CYP2A7 gene contains four single-nucleotide polymorphisms (SNPs) that cause missense mutations and have minor allele frequencies (MAFs) above 0.5. This means that the resulting amino acid changes occur in the majority of humans. In a previous study, we employed the reference standard sequence (called CYP2A7*1 in P450 nomenclature). For the present study, we created another CYP2A7 sequence that contains all four amino acid changes (Cys311, Glu169, Gly479, and Arg274) and labeled it CYP2A7-WT. Thus, it was the aim of this study to identify new substrates and inhibitors of CYP2A7 and to compare the properties of CYP2A7-WT with CYP2A7*1. We found several new proluciferin probe substrates for both enzyme variants (we also performed in silico studies to understand the activity difference between CYP2A7-WT and CYP2A7*1 on specific substrates), and we show that while they do not act on the standard CYP2A6 substrates nicotine, coumarin, or 7-ethoxycoumarin, both can hydroxylate diclofenac (as can CYP2A6). Moreover, we found ketoconazole, 1-benzylimidazole, and letrozole to be CYP2A7 inhibitors.
Databáze: MEDLINE
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