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Review ArticleReview Article

Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology

F. Peter Guengerich and Qian Cheng
Qiang Ma, ASSOCIATE EDITOR
Pharmacological Reviews September 2011, 63 (3) 684-699; DOI: https://doi.org/10.1124/pr.110.003525
F. Peter Guengerich
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee
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Qian Cheng
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee
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Qiang Ma
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee
Roles: ASSOCIATE EDITOR
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Abstract

As a result of technical advances in recombinant DNA technology and nucleotide sequencing, entire genome sequences have become available in the past decade and offer potential in understanding diseases. However, a central problem in the biochemical sciences is that the functions of only a fraction of the genes/proteins are known, and this is also an issue in pharmacology. This review is focused on issues related to the functions of cytochrome P450 (P450) enzymes. P450 functions can be categorized in several groups: 1) Some P450s have critical roles in the metabolism of endogenous substrates (e.g., sterols and fat-soluble vitamins). 2) Some P450s are not generally critical to normal physiology but function in relatively nonselective protection from the many xenobiotic chemicals to which mammals (including humans) are exposed in their diets [as well as more anthropomorphic chemicals (e.g., drugs, pesticides)]. 3) Some P450s have not been extensively studied and are termed “orphans” here. With regard to elucidation of any physiological functions of the orphan P450s, the major subject of this review, it is clear that simple trial-and-error approaches with individual substrate candidates will not be very productive in addressing questions about function. A series of liquid chromatography/mass spectrometry/informatics approaches are discussed, along with some successes with both human and bacterial P450s. Current information on what are still considered “orphan” P450s is presented. The potential for application of some of these approaches to other enzyme systems is also discussed.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.003525.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (3)
Pharmacological Reviews
Vol. 63, Issue 3
1 Sep 2011
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Review ArticleReview Article

Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology

F. Peter Guengerich and Qian Cheng
Pharmacological Reviews September 1, 2011, 63 (3) 684-699; DOI: https://doi.org/10.1124/pr.110.003525

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Review ArticleReview Article

Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology

F. Peter Guengerich and Qian Cheng
Pharmacological Reviews September 1, 2011, 63 (3) 684-699; DOI: https://doi.org/10.1124/pr.110.003525
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  • Article
    • Abstract
    • I. Introduction
    • II. Current Views of the Functions of P450s
    • III. Approaches to Deorphanization
    • IV. Current Status of Cytochrome P450 Orphans
    • V. Extensions of Approaches to Other Enzymes
    • VI. Conclusions and Perspectives
    • Acknowledgments
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