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Current Drug Metabolism
ISSN (Print): 1389-2002
ISSN (Online): 1875-5453
DOI: 10.2174/1389200023337054      Price:  $58

The Cytochrome P450 Superfamily: Biochemistry, Evolution and Drug Metabolism in Humans

Author(s): P.B. Danielson
Pages 561-597 (37)
Cytochrome P450s comprise a superfamily of heme-thiolate proteins named for the spectral absorbance peak of their carbon-monoxide-bound species at 450 nm. Having been found in every class of organism, including Archaea, the P450 superfamily is believed to have originated from an ancestral gene that existed over 3 billion years ago. Repeated gene duplications have subsequently given rise to one of the largest of multigene families. These enzymes are notable both for the diversity of reactions that they catalyze and the range of chemically dissimilar substrates upon which they act. Cytochrome P450s support the oxidative, peroxidative and reductive metabolism of such endogenous and xenobiotic substrates as environmental pollutants, agrochemicals, plant allelochemicals, steroids, prostaglandins and fatty acids. In humans, cytochrome P450s are best know for their central role in phase I drug metabolism where they are of critical importance to two of the most significant problems in clinical pharmacology: drug interactions and interindividual variability in drug metabolism. Recent advances in our understanding of cytochrome P450-mediated drug metabolism have been accelerated as a result of an increasing emphasis on functional genomic approaches to P450 research. While human cytochrome P450 databases have swelled with a flood of new human sequence variants, the functional characterization of the corresponding gene products has not kept pace. In response researchers have begun to apply the tools of proteomics as well as homology-based and ab initio modeling to salient questions of cytochrome P450 structure/function. This review examines the latest advances in our understanding of human cytochrome P450s.
University of Denver,Department of Biological Sciences, 2101 East Wesley Avenue, Rm. 211,Denver, Colorado 80210, USA.