Biochemical and Biophysical Research Communications
ReviewFunction of human cytochrome P450s: Characterization of the orphans
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.
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