Abstract
The cytochrome P450 enzymes active in drug metabolism are highly polymorphic. Most allelic variants have been described for enzymes encoded by the cytochrome P450 family 2 (CYP2) gene family, which has 252 different alleles. The intronic polymorphisms in the cytochrome P450 genes account for only a small number of the important variant alleles; however, the most important ones are CYP2D6*4 and CYP2D6*41, which cause abolished and reduced CYP2D6 activity, respectively, and CYP3A5*3 and CYP3A5*5, common in Caucasian populations, which cause almost null activity. Their discoveries have been based on phenotypic alterations within individuals in a population, and their identification has, in several cases, been difficult and taken a long time. In light of the next-generation sequencing projects, it is anticipated that further alleles with intronic mutations will be identified that can explain the hitherto unidentified genetic basis of inter-individual differences in cytochrome P450-mediated drug and steroid metabolism.
Highlights
The cytochrome P450 (CYP) enzymes are active in the metabolism of xenobiotics, as well as of endogenous compounds
The CYP enzymes can be divided into two major classes: those that are active in the metabolism of exogenous chemicals, preferentially members of families 1–3, and those that are mainly active in the metabolism of endogenous compounds, in particular steroids, fatty acids, cholesterol and cholesterol derivatives
Other genes that are highly polymorphic in this gene family are CYP2C9 and CYP2C19, while other genes with important functional polymorphisms are CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2J2, CYP2R1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, CYP4A22, CYP4B1, CYP4F2, CYP5A1, CYP8A1, CYP19A1, CYP21A2 and CYP26A1
Summary
The cytochrome P450 (CYP) enzymes are active in the metabolism of xenobiotics, as well as of endogenous compounds. genes coding for active CYP enzymes and pseudogenes have been identified. Many of the active genes are highly polymorphic, as summarised on the Human Cytochrome P450 Allele Nomenclature (CYP-allele) website (http://www.cypalleles.ki.se/), and several hundred different variants have been identified. This includes about 400 different alleles with non-synonymous mutations or important functional mutations; 79, 253, 34 and 25 variants are present in gene families CYP1, CYP2, CYP3 and CYP4, respectively (www.cypalleles.ki.se). The CYP alleles known so far have generally not been identified through large genomic sequencing projects. Results from such studies are expected to be published in the near future and to yield a high number of novel polymorphic loci. It is evident that thousands of mutations are localised in introns and gene-flanking regions which are not present in the current databases (Frank Nylen, unpublished observations)
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