Intronic polymorphisms of cytochromes P450

The cytochrome P450 (CYP) enzymes are active in the metabolism of xenobiotics, as well as of endogenous compounds. In the human genome, 57 genes coding for active CYP enzymes and 58 pseudogenes have been identified. 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. 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/ webcite, and several hundred different variants have been identified. The most polymorphic gene among CYPs important for the metabolism of exogenous compounds is the CYP2D6 gene, for which about 80 different allelic variants have been described. 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. The highest number of variant alleles among the cytochromes P450 is seen in CYP21A2, which encodes the steroid 21 hydroxylase, for which 119 rare variants have been identified. In addition to the CYPs, NADPH cytochrome P450 reductase (POR), the electron donor for CYP enzymes, has been shown to have important polymorphic variants http://www.cypalleles.ki.se/por.htm webcite and, recently, the second electron donor, cytochrome b5, has also been shown to exhibit functional polymorphisms, [1] although functionally variant alleles are rare.In the field of pharmacogenetics, emphasis is put on the functionally important polymorphic CYP variants. This includes about 400 different alleles with non-synonymous mutations or important functional mutatio