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Int. J. Mol. Sci. 2017, 18(7), 1553; doi:10.3390/ijms18071553

Inhibitory Effects of Trapping Agents of Sulfur Drug Reactive Intermediates against Major Human Cytochrome P450 Isoforms

1
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way (MS 412a), South San Francisco, CA 94080, USA
2
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94143, USA
3
Department of Drug Metabolism and Pharmacokinetics, MicroConstants, Inc., San Diego, CA 92121, USA
4
Department of Drug Metabolism and Pharmacokinetics, Plexxikon Inc., Berkeley, CA 94710, USA
5
Department of Drug Metabolism and Pharmacokinetics, MyoKardia, Inc., South San Francisco, CA 94080, USA
6
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris CEDEX 06, France
*
Author to whom correspondence should be addressed.
Received: 19 June 2017 / Revised: 11 July 2017 / Accepted: 14 July 2017 / Published: 20 July 2017
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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Abstract

In some cases, the formation of reactive species from the metabolism of xenobiotics has been linked to toxicity and therefore it is imperative to detect potential bioactivation for candidate drugs during drug discovery. Reactive species can covalently bind to trapping agents in in vitro incubations of compound with human liver microsomes (HLM) fortified with β-nicotinamide adenine dinucleotide phosphate (NADPH), resulting in a stable conjugate of trapping agent and reactive species, thereby facilitating analytical detection and providing evidence of short-lived reactive metabolites. Since reactive metabolites are typically generated by cytochrome P450 (CYP) oxidation, it is important to ensure high concentrations of trapping agents are not inhibiting the activities of CYP isoforms. Here we assessed the inhibitory properties of fourteen trapping agents against the major human CYP isoforms (CYP1A2, 2C9, 2C19, 2D6 and 3A). Based on our findings, eleven trapping agents displayed inhibition, three of which had IC50 values less than 1 mM (2-mercaptoethanol, N-methylmaleimide and N-ethylmaleimide (NEM)). Three trapping agents (dimedone, N-acetyl-lysine and arsenite) did not inhibit CYP isoforms at concentrations tested. To illustrate effects of CYP inhibition by trapping agents on reactive intermediate trapping, an example drug (ticlopidine) and trapping agent (NEM) were chosen for further studies. For the same amount of ticlopidine (1 μM), increasing concentrations of the trapping agent NEM (0.007–40 mM) resulted in a bell-shaped response curve of NEM-trapped ticlopidine S-oxide (TSO-NEM), due to CYP inhibition by NEM. Thus, trapping studies should be designed to include several concentrations of trapping agent to ensure optimal trapping of reactive metabolites. View Full-Text
Keywords: cytochrome P450; bioactivation; trapping agents; reactive metabolites; CYP inhibition; sulfur drug reactive intermediates cytochrome P450; bioactivation; trapping agents; reactive metabolites; CYP inhibition; sulfur drug reactive intermediates
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Sodhi, J.K.; Delarosa, E.M.; Halladay, J.S.; Driscoll, J.P.; Mulder, T.; Dansette, P.M.; Khojasteh, S.C. Inhibitory Effects of Trapping Agents of Sulfur Drug Reactive Intermediates against Major Human Cytochrome P450 Isoforms. Int. J. Mol. Sci. 2017, 18, 1553.

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Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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