Purification, Expression, Mechanism, and Relevance to Drugs
Abstract
Today cytochrome P450 (P450) research is accepted as an integral part of drug development and discovery. Work leading to this point included biochemical studies on P450 in experimental animal models and application to human systems. The development of recombinant expression systems has been an important part of the progress, and in this article we describe some recently developed bacterial systems that can be used for the production of metabolites, genotoxicity testing, and screening in random mutagenesis work. Rate-limiting aspects of P450 reactions vary with particular systems, and further investigations are in order. Non-ionic detergents have been utilized widely in P450 purification work; these compounds are now shown to be substrates for P450s. These oxidations are not only of fundamental interest in expanding the repertoire of P450 substrates but have significance in light of human exposure to these compounds.
Footnotes
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Send reprint requests to: Prof. F. P. Guengerich, Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. e-mail: guengerich{at}toxicology.mc.vanderbilt.edu
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↵1 Current address: Schering-Plough Corp., 144 Route 94, P.O. Box 32, Lafayette, NJ 07848.
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The work described here was supported in part by United States Public Health Service grants R35 CA44353, P30 ES00267, T32 ES07028, T32 GM07347, and F32 CA74492; by grants from the Ministry of Education, Science, and Culture of Japan; the Ministry of Health and Welfare of Japan; the Developmental and Creative Studies from the Osaka Prefectural Government; and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN.
- Abbreviations used are::
- P450
- cytochrome P450 (also termed “heme-thiolate protein P450” (Palmer and Reedijk, 1992))
- The American Society for Pharmacology and Experimental Therapeutics
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