Cytochrome P450s in the development of target-based anticancer drugs

Abstract Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to in...

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Bibliographic Details
Published in:Cancer letters 2008-01, Vol.259 (1), p.1-15
Main Authors: Purnapatre, Kedar, Khattar, Sunil K, Saini, Kulvinder Singh
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Biotransformation
Cancer
Cloning, Molecular
CYP
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Drug Design
Drug discovery
Drug Evaluation, Preclinical
Drug Interactions
Drug Resistance, Neoplasm
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Expression
Genes
Hematology, Oncology and Palliative Medicine
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - metabolism
Pharmaceutical industry
Pharmacogenetics
Pharmacokinetics
Recombinant P450
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - metabolism
Reproducibility of Results
Rodents
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Summary:Abstract Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug–drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2007.10.024