Abstract
By assessing how drug/new chemical entity (NCE) cytotoxicity is affected when their metabolic pathways are inhibited or activated, the metabolic pathways that activate versus detoxify drugs/NCEs can be identified. Reactive metabolites contributing to cytotoxicity can also be identified. In the following, the drug metabolizing enzyme inhibitors and activators used in vitro with freshly isolated rat hepatocytes for the accelerated cytotoxicity mechanism screening (ACMS) of drugs/NCEs (a technique used in our laboratory) are reviewed and, this technique is useful for determining in vivo rat hepatotoxicity mechanisms. The enzyme inhibitors/activators have been chosen on the basis of their selectivity, modulator effectiveness, and their lack of toxicity. The use of these inhibitors/activators with human hepatocytes or subcellular fractions for assessing human hepatotoxicity mechanisms is also reviewed.
Keywords: cytochrome p-450, hepatotoxicity, glucuronosyltransferase, arylamine n-acetyltransferase, sulfotransferases, glutathione transferase, coenzyme a-transferases, enzyme Inhibitors
Current Drug Metabolism
Title: Accelerated Cytotoxicity Mechanism Screening Using Drug Metabolising Enzyme Modulators
Volume: 6 Issue: 2
Author(s): P. J. O'Brien and A. G. Siraki
Affiliation:
Keywords: cytochrome p-450, hepatotoxicity, glucuronosyltransferase, arylamine n-acetyltransferase, sulfotransferases, glutathione transferase, coenzyme a-transferases, enzyme Inhibitors
Abstract: By assessing how drug/new chemical entity (NCE) cytotoxicity is affected when their metabolic pathways are inhibited or activated, the metabolic pathways that activate versus detoxify drugs/NCEs can be identified. Reactive metabolites contributing to cytotoxicity can also be identified. In the following, the drug metabolizing enzyme inhibitors and activators used in vitro with freshly isolated rat hepatocytes for the accelerated cytotoxicity mechanism screening (ACMS) of drugs/NCEs (a technique used in our laboratory) are reviewed and, this technique is useful for determining in vivo rat hepatotoxicity mechanisms. The enzyme inhibitors/activators have been chosen on the basis of their selectivity, modulator effectiveness, and their lack of toxicity. The use of these inhibitors/activators with human hepatocytes or subcellular fractions for assessing human hepatotoxicity mechanisms is also reviewed.
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Cite this article as:
O'Brien J. P. and Siraki G. A., Accelerated Cytotoxicity Mechanism Screening Using Drug Metabolising Enzyme Modulators, Current Drug Metabolism 2005; 6 (2) . https://dx.doi.org/10.2174/1389200053586082
DOI https://dx.doi.org/10.2174/1389200053586082 |
Print ISSN 1389-2002 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5453 |
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