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.â€‚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.â€‚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.â€‚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.â€‚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.
DMPK, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines , SÃ¶dertÃ¤lje , Sweden.
This article was published in the following journal.
Name: Xenobiotica; the fate of foreign compounds in biological systems
- 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
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.
The octapeptide amide of bovine angiotensin II used to increase blood pressure by vasoconstriction.
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).
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.
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.
An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediat...
A series of TRPV1 agonists with amide, reverse amide, and thiourea groups in the B-region and their corresponding Î±-methylated analogues were investigated. Whereas the Î±-methylation of the amide B-r...
In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, a series of nineteen analogues (1b-5) of racemic -gingerol (1a) was synthesized and tested o...
The capsaicin-, heat-, and proton-activated ion channel TRPV1, a member of the transient receptor potential cation channel family is a polymodal nociceptor. For almost a decade, TRPV1 has been explore...
The cloning of the first sensory Transient Receptor Potential (TRP) channel, TRPVanilloid 1 (TRPV1) in 1997, initiated a new era of pain research and coincided with the Decade of Pain Control and Rese...
The purpose of this study is to determine the dose of the GLP-1 receptor antagonist exendin(9-39) which blocks the insulinotropic action of synthetic GLP-1 by at least 95%.
Despite the success of the triptan class of drugs, approximately 60% of patients who take medication at the moderate to severe pain stage of acute migraine, still have pain of mild or grea...
To characterize features of metabolic syndrome in volunteers. To undertake a randomised trial to determine whether treatment with a statin improves muscle microvascular blood flow.
This research is being done to see if giving a hormone called GLP-1 can improve heart function and reduce length of stay in the Cardiac Surgical Intensive Care Unit (CSICU) in people who h...
This project investigates the effect of ACE-inhibition on cellular metabolism by gene expression profiling of human muscle tissue, obtained by biopsy prior to and after ramipril intake....