Why Is Quinidine an Inhibitor of Cytochrome P450 2D6?

Abstract

had only a minor effect on the inhibition of bufuralol 1-hydroxylation and dextromethorphan O-demethylation and on binding. In contrast to the wild-type enzyme, a number of the mutants studied were found to be able to metabolize quinidine. E216F produced O-demethylated quinidine, and F120A and E216Q/D301Q produced both O-demethylated quinidine and 3-hydroxyquinidine metabolites. Homology modeling and molecular docking were used to predict the modes of quinidine binding to the wild-type and mutant enzymes; these were able to rationalize the experimental observations.Human cytochrome P450 2D6 (CYP2D6) 4 plays a central role in drug metabolism, metabolizing Ͼ30% of the most commonly prescribed drugs (1). The CYP2D6 gene is highly polymorphic, leading to wide interindividual and ethnic differences in CYP2D6-mediated drug metabolism (2-4). Cytochrome P450-drug and drug-drug interactions involving CYP2D6 ligands are thus a prime consideration in the development of new drugs, emphasizing the importance of a detailed understanding of the factors that govern the substrate specificity of this enzyme.Quinidine is not metabolized by CYP2D6 and has long been established as a potent competitive inhibitor of the enzyme (5-9). The fact that quinidine is an inhibitor rather than a substrate is intriguing because it produces a classical type I binding spectrum with CYP2D6 (10) that is usually associated with the binding of substrate molecules (11). In addition, quinidine possesses a number of features normally associated with CYP2D6 substrates, including a basic nitrogen atom, a flat hydrophobic region, and a negative molecular electrostatic potential (12). Studies of the relationship between structure and inhibitory activity for quinidine and its (less potent) stereoisomer quinine have been reported (13), but the protein-ligand interactions that are responsible for the fact that quinidine can bind tightly, but not in an orientation favorable for catalysis, have not hitherto been established.

Crystal Structure of Human Cytochrome P450 2D6

“…Keizers et al (73) found that the same mutant abolished the O-demethylation of 7-methoxy-4-(aminomethyl)-coumarin, whereas bufuralol metabolism was unaffected. Very recently, McLaughlin et al (74) reported that the F120A mutation changed the role of quinidine from being a potent inhibitor to becoming a substrate. The position of Phe-120 in the crystal structure is in clear agreement with these studies.…”

Molecular modelling of human CYP2D6 and molecular docking of a series of ajmalicine- and quinidine-like inhibitors

“…In particular the hydroxyl group of quinidine (rather than the basic nitrogen atom, known to be relevant for the interactions with CYP2D6) forms the dominant interaction with Glu216 [16].…”

“…The cavity entrance is bordered by a number of long charged/hydrophilic side chains from the F helix (Gln210, Glu211, Lys214, and Arg221) and residues from the region between the two strands of ␤ sheet 4 (side chains of Ala482 and Ser486 and main chain atoms of Val485), with the side chains of Asp179 (helix E) and Thr312 (helix I) also in the vicinity [15]. Among the residues of the cavity, Phe120, Glu216, Asp301, and Met374, in particular are considered to be the most relevant for the inhibitor and substrate binding [16].…”

Control by Substrate of the Cytochrome P450-Dependent Redox Machinery: Mechanistic Insights

“…However, only 39% of the amount of NADPH consumed was found to serve in product formation, the remainder being utilized in the formation of H 2 O 2 and water [146]. Tight binding of the inhibitor quinidine, generating a mixture of low-and high-spin CYP2D6 [145][146][147], gave origin to a cyclic voltammetric profile aberrant from that observed with prototypic substrates [141]. Docking might be influential on the release of extra water in incubations with reconstituted hemoprotein, though there is no evidence for biotransformation of the nitrogenous base [146].…”