Drug Metabolism: Evolution


Advances in molecular biology and genetics have given us a much better understanding of the evolution of drug metabolism. Genes encoding drug‐metabolizing enzymes, as well as some drug receptors and transporters, have functioned in many signal transduction pathways in bacteria and yeast and, more recently, in countless critical life processes in plants and animals – events that emerged millions of years before the establishment of pharmaceutical companies and drug stores.

Keywords: drug metabolism; evolution; receptors; transporters; polymorphisms; human populations

Figure 1.

Diagram of the fate of drugs (R) entering the cell. Drugs might enter the cell by either passive diffusion or active transporters. Either the parent nonmetabolized drug or metabolite reaches its clinical target (efficacy), or the drug or metabolite causes toxicity via perturbation of the cell cycle or covalent binding. Reception mechanisms are able to detect the drug as a ‘signal’, and sometimes can up‐ or downregulate Phase I and Phase II drug‐metabolizing enzymes (Nebert, ). The encircled plus and minus signs denote positive and negative regulation respectively. Transporter proteins can also assist in moving the parent drug and metabolites out of the cell. O=Oxygen atom; conjugate=any polar moiety that is transferred to Phase I products by Phase II DMEs. (Reproduced with permission from publisher, Nebert .)

Figure 2.

Summary of the probable relationship between drug‐metabolizing enzymes (DMEs) and all nonpeptide endogenous ligands that stimulate signal transduction pathways, affecting innumerable critical cellular functions. (Reproduced with permission from publisher; modified from Nebert .)



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Further Reading

Courvalin P and Trieu‐Cuot P (2001) Minimizing potential resistance: the molecular view. Clinical Infectious Diseases 33(supplement 3): S157–S160.

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Web Links

Cytochrome P450 Homepage http://drnelson.utmem.edu/cytochromeP450.html

OMIM Online Mendelian Inheritance in Man. This database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and colleagues at Johns Hopkins and elsewhere, and developed for the World Wide Web by the National Center for Biotechnology Information. The database contains textual information, pictures and reference information. It also contains copious links to NCBI's Entrez database of MEDLINE articles and sequence information. The OMIM Morbid Map, a catalog of genetic disease and their cytogenetic map locations arranged alphabetically by disease, is now also available. http://www.ncbi.nlm.nih.gov/omim/

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Nebert, Daniel W(Sep 2006) Drug Metabolism: Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006143]