MERITS AND LIMITATIONS OF RECOMBINANT MODELS FOR THE STUDY OF HUMAN P450-MEDIATED DRUG METABOLISM AND TOXICITY: AN INTRALABORATORY COMPARISON
| Autor: | Steven P. Hanlon, Brian Burchell, M Bandera, Denggao Yao, Michael P. Pritchard, Shaohong Ding, Lesley A. McLaughlin, C R Wolf, Thomas Friedberg |
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| Rok vydání: | 1999 |
| Předmět: |
Drug-Related Side Effects and Adverse Reactions
Molecular Sequence Data Gene Expression Biology digestive system Isozyme law.invention chemistry.chemical_compound Cytochrome P-450 Enzyme System law Animals Humans Pharmacology (medical) Amino Acid Sequence General Pharmacology Toxicology and Pharmaceutics Toxication Sequence Homology Amino Acid Intralaboratory Recombinant Proteins Pharmaceutical Preparations Biochemistry chemistry Drug development Environmental toxicology Toxicity Recombinant DNA Drug metabolism |
| Zdroj: | Drug Metabolism Reviews. 31:523-544 |
| ISSN: | 1097-9883 0360-2532 |
| Popis: | A wide variety of pharmacological and toxicological properties of drugs are determined by cytochrome P450-mediated metabolism. Characterization of these pathways and of the P450 isoenzymes involved constitutes an essential part of drug development. Similarly, because P450s are catalyzing the toxication and detoxication of environmental pollutants, an understanding of these reactions facilitates risk assessment in environmental toxicology. Recently, a variety of recombinant expression systems has been employed to study the role of human P450s in these reactions. These include insect, bacterial, yeast, and mammalian models. As these were developed and characterized by different laboratories, evaluation of their merits and limitations is inherently difficult. To resolve this problem, we have established and characterized the latter three systems and present the key results here. In general, the catalytic properties of P450 isozymes in the various models were rather similar. However, taking technical considerations into account as well as the high level of functional expression of P450s achieved in bacteria make this system ideally suited for drug metabolism research, including the generation of milligram quantities of metabolites for structural determinations. For toxicological studies, however, expression of P450s in mammalian cells was most appropriate. This is exemplified here by studies into the role of human P450s in the activation and inactivation of chemotherapeutic drugs. |
| Databáze: | OpenAIRE |
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