Review
Function of human cytochrome P450s: Characterization of the orphans

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Abstract

The human genome has now been established to contain 57 cytochrome P450 genes. The proteins can be grouped into categories of types of substrates, including sterols, fatty acids, eicosanoids, and fat-soluble vitamins. Some P450s have also been demonstrated to have significant roles in the metabolism of drugs and chemicals. In addition to these, at least 13 can be considered to still be without apparent function with endogenous or xenobiotic substrates. The current list includes P450s 2A7, 2S1, 2U1, 2W1, 3A43, 4A22, 4F11, 4F22, 4V2, 4X1, 4Z1, 20A1, and 27C1. Limited information is available about the sites of mRNA expression of some of these orphans. Some strategies for characterization are discussed.

Section snippets

General issues with P450 orphans

The human P450s listed under “unknown” can be termed “orphans” in the sense of the use of the word for describing receptor proteins without known ligands [20]. The classification presented in Table 1 is somewhat arbitrary, in that some evidence is available about reactions catalyzed by these P450s but it is either only quantitative or the reactions are considered too slow to make a major contribution.

A significant amount of mRNA expression information is available for many, but not all, of the

Approaches to defining functions of orphans

In traditional biochemistry (Fig. 1), the starting point is usually an existing in vivo reaction. If one could develop an assay, the enzyme could at least theoretically be purified. Later (after ∼1980), the cDNA and gene could be cloned. However, today the human genome is in hand and the genomes of many other organisms are rapidly becoming available. The problem is that the functions of the majority of gene products are unknown, and new strategies and paradigms are needed to address the problem.

Current status of orphans

Limited information about the sites of mRNA expression of several of the orphan P450s has been published, although some of it is inconsistent in the literature (Table 2).

Whether P450 2A7 is expressed or not is unclear. In an earlier work, Gonzalez’s laboratory expressed the protein in a vaccinia system but no heme was incorporated [43]. Crossover of the P450 2A6 and 2A7 genes has been reported to yield proteins [21], [22].

P450 2S1 mRNA expression has been detected in several tissues (Table 2).

Conclusions

We have grouped 13 of the 57 human P450s as orphans. This is a subjective classification and is based on the limited knowledge about the them at the present time, with no conclusion about importance. Some of these proteins have been reported to show low rates of activity towards arachidonic acid and retinoic acid, but interpretations about biological relevance must be considered premature. The limited activity of P450s 3A43 and 4F11 towards some model xenobiotics is also low [31], [34], [37],

Acknowledgment

We thank K. Trisler for assistance in preparation of the manuscript.

References (47)

  • G. Smith et al.

    Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases

    Lancet

    (2003)
  • D. Choudhary et al.

    Expression patterns of mouse and human CYP orthologs (families 1-4) during development and in different adult tissues

    Arch. Biochem. Biophys.

    (2005)
  • M. Karlgren et al.

    Characterization and tissue distribution of a novel human cytochrome P450-CYP2U1

    Biochem. Biophys. Res. Commun.

    (2004)
  • S.S. Chuang et al.

    CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes ω- and (ω-1)-hydroxylation of fatty acids

    J. Biol. Chem.

    (2004)
  • A. Westlind et al.

    Cloning and tissue distribution of a novel human cytochrome P450 of the CYP3A subfamily, CYP3A43

    Biochem. Biophys. Res. Commun.

    (2001)
  • A. Bellamine et al.

    Characterization of the CYP4A11 gene, a second CYP4A gene in humans

    Arch. Biochem. Biophys.

    (2003)
  • U. Savas et al.

    Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone

    Arch. Biochem. Biophys.

    (2003)
  • A. Kalsotra et al.

    Expression and characterization of human cytochrome P450 4F11: Putative role in the metabolism of therapeutic drugs and eicosanoids

    Toxicol. Appl. Pharmacol.

    (2004)
  • A. Li et al.

    Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2

    Am. J. Hum. Genet.

    (2004)
  • J. Bylund et al.

    Identification of a novel cytochrome P450, CYP4X1, with unique localization specific to the brain

    Biochem. Biophys. Res. Commun.

    (2002)
  • U. Savas et al.

    Conditional regulation of the human CYP4X1 and CYP4Z1 genes

    Arch. Biochem. Biophys.

    (2005)
  • D. Choudhary et al.

    Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues

    Arch. Biochem. Biophys.

    (2003)
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