Inhibition of Cytochrome P450 Enzymes by Quinones and Anthraquinones

Abstract

In silico docking studies and quantitative structure–activity relationship analysis of a number of in-house cytochrome P450 inhibitors have revealed important structural characteristics that are required for a molecule to function as a good inhibitor of P450 enzymes 1A1, 1A2, 2B1, and/or 2A6. These insights were incorporated into the design of pharmacophores used for a 2D search of the Chinese medicine database. Emodin, a natural anthraquinone isolated from Rheum emodi and known to be metabolized by cytochrome P450 enzymes, was one of the hits and was used as the lead compound. Emodin was found to inhibit P450s 1A1, 1A2, and 2B1 with IC50 values of 12.25, 3.73, and 14.89 μM, respectively. On the basis of the emodin molecular structure, further similarity searches of the PubChem and ZINC chemical databases were conducted resulting in the identification of 12 emodin analogues for testing against P450s 1A1-, 1A2-, 2B1-, and 2A6-dependent activities. 1-Amino-4-chloro-2-methylan-thracene-9,10-dione (compound 1) showed the best inhibition potency for P450 1A1 with an IC50 value of 0.40 μM. 1-Amino-4-chloro-2-methylanthracene-9,10-dione (compound 1) and 1-amino-4-hydroxyanthracene-9,10-dione (compound 2) both inhibited P450 1A2 with the same IC50 value of 0.53 μM. In addition, compound 1 acted as a mechanism-based inhibitor of cytochrome P450s 1A1 and 1A2 with KI and Kinactivation values of 5.38 μM and 1.57 min−1 for P450 1A1 and 0.50 μM and 0.08 min−1 for P450 1A2. 2,6-Di-tert-butyl-5-hydroxynaphthalene-1,4-dione (compound 8) directly inhibited P450 2B1 with good selectivity and inhibition potency (IC50 = 5.66 μM). Docking studies using the 3D structures of the enzymes were carried out on all of the compounds. The binding modes of these compounds revealed the structural characteristics responsible for their potency and selectivity. Compound 1, which is structurally similar to compound 2 in the presence of an amino group at position 1, showed a difference in the mechanism of inhibition toward P450s 1A1 and 1A2. The mechanism-based inhibition seen for compound 1 may be attributed to the presence of the methyl group at the 2-position, in close proximity to the amino group. Compound 2, which is otherwise similar, lacks that methyl moiety and did not show mechanism-based inhibition.

Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes

“…1). It has been reported that PHA-like chemicals are likely to be potent inhibitors of CYP1A, CYP1B, CYP2C, and CYP3A (Sridhar et al, 2012), and MDP-containing chemicals tend to inhibit CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A (Murray, 2000;Fang et al, 2010). With the PHA-like and MDP-containing structural characters, the spectrum of inhibition of SAG is consistent with the previous reports.…”

“…As reported, both PAH-like and MDP-containing chemicals are structural alerts for the modulation of CYP activities (Murray, 2000;Shimada, 2006). For example, quinones (Sridhar et al, 2012) and noscapine (Fang et al, 2010) have been demonstrated as strong modulators of CYP enzymes. Indeed, SAG has been shown to induce the CYP1A gene expression via aryl hydrocarbon signal pathway (Karp et al, 2005), and inhibit human CYP1A1 and CYP1A2 (Vrba et al, 2004;Zdarilová et al, 2006), as well as rat CYP1A1, CYP1A2, CYP2D1, CYP2E1 and CYP3A1 (Reddy and Das, 2008;Eruvaram and Das, 2009).…”

Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

“…BAs were derived from the catabolism of cholesterol, and BAs pool could be divided into primary and secondary BAs based on biological source. In the progress of primary BAs biosynthesis, P450 enzymes including CYP7A1, CYP8B1, CYP27A1, and CYP7B1 were involved in de Aguiar Vallim et al (2013), and there has been literatures reporting that HSW and anthraquinones in it would inhibit P450s involved in metabolism of pharmaceuticals (Sridhar et al, 2012; Wang et al, 2015). However, there was little study focusing on the influence of HSW to P450s involved in primary BAs biosynthesis in pathogenesis of liver injury.…”

Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

“…103,161−163 For example, 4-hydroxytamoxifen and raloxifene were found to be potent mechanism-based inactivators of P450 as a result of quinone-mediated alkylation of the apoprotein. 164−166 With raloxifene, analysis of the P450 3A4 peptide showed that Cys239 was the site of the raloxifene extended quinone reaction.…”