Metabolic profiling of TRPV1 antagonists of the benzothiazole amide series: implications for in vitro genotoxicity assessment.
Summary of "Metabolic profiling of TRPV1 antagonists of the benzothiazole amide series: implications for in vitro genotoxicity assessment."
1. In vitro metabolic profiling and in vitro genotoxicity assessment are important aspects of the drug discovery program as they eliminate harmful compounds from further development. In standard in vitro genotoxicity testing, induced rat liver S9 is used as an exogenous bio-activation system for detecting promutagens. In this study we show that rat liver S9 is an insufficient system regarding the conversion of TRPV1 antagonists of the benzothiazole amide series into relevant in vivo metabolites. 2. Human and rat hepatocyte experiments demonstrated generation of an aryl amine metabolite that was subsequently N-acetylated. The hydrolyzed metabolites as well as the parent compound were also metabolized into glutathione (GSH) conjugates. Rat liver S9 exhibited a very low amide hydrolysis capacity and no formation of GSH conjugates when supplemented with NADPH and GSH. 3. The discrepancy in metabolic capability between hepatocytes and rat liver S9 led to confounding results in in vitro genotoxicity assessment for this chemical class as judged by the results of Ames test, mouse lymphoma assay, SOS/umu test and Comet assay in rat hepatocytes. 4. This study highlights the pivotal role that understanding the mechanism of metabolite formation has in interpreting as well as designing reliable and relevant in vitro genotoxicity experiments.
Affiliation
DMPK, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines , Södertälje , Sweden.
Journal Details
This article was published in the following journal.
Name: Xenobiotica; the fate of foreign compounds in biological systems
ISSN: 1366-5928
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22867274
- DOI: http://dx.doi.org/10.3109/00498254.2012.708459
Medical and Biotech [MESH] Definitions
Amide Synthases
Enzymes that catalyze the joining of either ammonia or an amide with another molecule, in which the linkage is in the form of a carbon-nitrogen bond. EC 6.3.1.
Angiotensin Amide
The octapeptide amide of bovine angiotensin II used to increase blood pressure by vasoconstriction.
Aroclors
Industrial chemicals which have become widespread environmental pollutants. Each aroclor is a mixture of chlorinated biphenyls (1200 series) or chlorinated terphenyls (5400 series) or a combination of both (4400 series).
Dithiazanine
3-Ethyl-2-(5-(3-ethyl-2-benzothiazolinylidene)-1,3- pentadienyl)benzothiazolium. A benzothiazole that was formerly used as an antinematodal agent and is currently used as a fluorescent dye.
Purines
A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include ADENINE and GUANINE, constituents of nucleic acids, as well as many alkaloids such as CAFFEINE and THEOPHYLLINE. Uric acid is the metabolic end product of purine metabolism.
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