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

被引:78
作者
Guengerich, F. Peter [1 ,2 ]
Cheng, Qian
机构
[1] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Ctr Mol Toxicol, Nashville, TN 37232 USA
基金
美国国家卫生研究院;
关键词
CORNEO-RETINAL DYSTROPHY; MASS-SPECTROMETRY DATA; HETEROLOGOUS EXPRESSION; TISSUE DISTRIBUTION; HUMAN LIVER; MICROSOMAL CYTOCHROME-P-450; DRUG-INTERACTIONS; CDNA CLONING; PROFILE DATA; FATTY-ACIDS;
D O I
10.1124/pr.110.003525
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:684 / 699
页数:16
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