Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6

Abstract

ABSTRACT:Human CYP2A6 catalyzes the metabolism of nicotine, cotinine, and coumarin as well as some pharmaceutical drugs. CYP2A6 is highly expressed in liver and, also, in brain and steroid-related tissues. In this study, we investigated the inhibitory effects of neurotransmitters and steroid hormones on CYP2A6 activity. We found that coumarin 7-hydroxylation and cotinine 3-hydroxylation by recombinant CYP2A6 expressed in baculovirus-infected insect cells were competitively inhibited by tryptamine (both Thus, we found that some neurotransmitters inhibit CYP2A6 activity, being related with inter-and intraindividual differences in CYP2A6-dependent metabolism. The inhibitory effects of steroid hormones on aldehyde oxidase may also contribute to interindividual differences in nicotine metabolism.

Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity

“…Tryptamine inhibits CYP2A6 at K i values in the range of 0.2-1.9 lM (Higashi et al 2007;Zhang et al 2001). However, this inhibitor is not very selective because it inhibits CYP1A2 at a K i of 1.7 lM (Zhang et al 2001).…”

Rational design of novel CYP2A6 inhibitors

“…Previous studies have also shown differences in the CYP2A6 inhibitory effect of some neurotransmitter and steroid hormones 33 and isoflavones 34 depending on whether coumarin or nicotine was used as a substrate. Thus, the inhibitory characteristics of a compound may vary depending on the substrate used, a well-known phenomenon for other CYP enzymes, especially CYP3A4.…”

“…In contrast, the K i values were more than 15-fold higher for nicotine oxidation for the compounds with a formyl substituent (1,2,24,33).…”

“…These compounds included three synthesized compounds (1,2,8) and the most potent inhibitors of coumarin 7-hydroxylation in each core (3,5,24,25,33). These compounds had formyl, alkyl amine or nitrile substituents.…”

Development of a New Predictive Model for Interactions with Human Cytochrome P450 2A6 Using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) Approach

“…Therefore, the generated PhE/SVM model was further challenged with a group of benzene and naphthalene derivatives and a series of neurotransmitters and steroids published by Rahnasto et al (26) and Higashi et al (64), respectively. These molecules were selected as external test sets 1 and 2, respectively, and the experimental IC 50 values measured by the inhibition of coumarin 7-hydroxylation were adopted to be consistent with the compound selections in the training set and the test set.…”