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In humans, the cytochrome P450 enzymes (CYP450s) are a superfamily of structurally-related heme-containing enzymes that play a central role in the oxidation or reduction of xenobiotics, including drugs, as well as a number of physiologically important compounds such as steroid hormones and eicosanoids. The biotransformation of drugs by the CYP450s can serve to activate or inactivate these compounds while increasing their water solubility and facilitating their elimination.
In humans, 18 CYP450 gene families (identified numerically) are subdivided into 43 structurally related subfamilies (indicated alphabetically) and a total of 59 active genes (identified numerically) have been identified that code for these membrane-bound enzymes that are localized in the smooth endoplasmic reticulum of liver, lung, intestine and brain cells (1).
The impact of CYP450 enzymes on the metabolism of currently marketed drugs is considerable. It has been estimated that "over 90% of drugs in common clinical use are metabolized by the CYP450 family of liver isoenzymes" (3). The CYP450s from families 1 through 3, which are least conserved through evolution, contribute significantly (70-80%) to phase I metabolism of a large number of currently prescribed and over-the counter medications (4, 5). These highly variable, or polymorphic, drug-metabolizing CYP450s have been shown in the literature to account for much of the high degree of inter-individual variability in drug response (2, 6, 7). In some individuals, this variability translates to an increased risk for the development of an adverse drug reaction (ADR) (7, 8, 9).
With the completion of the human genome sequencing project a well-characterized catalog of sequence variants for known key genes and superfamilies of genes, including the CYP450 genes, has become available. Nomenclature of the cytochrome P450s (http://drnelson.utmem.edu/CytochromeP450.html) begins with CYP followed by gene family number, subfamily letter and finally, the gene number (e.g. CYP2D6). Allelic designations for the highly polymorphic drug metabolizing CYP450 genes are indicated by a maximum of 4 characters starting with an Arabic numeral which are separated from the gene number by an asterisk (e.g.CYP2D6*9).
Polymorphisms in CYP450 genes from family 2, for example CYP2D6, with significant clinical relevance are associated with diminished, absent, or increased enzyme activity as a result of mutations in substrate recognition sites, a gene deletion, or multiple gene copies, respectively (1). Frequency distributions for the different variants of any given CYP450 gene vary across different ethnicities and races. For example, the "wild-type" or fully functional CYP2D6 alleles *1 and *2 together represent ~71% of known variation in the Caucasian population, whereas in Asian populations, these account for ~52% of the known CYP2D6 variation (3). Similarly, the reduced function allele, *10, is the most frequent (>50%) CYP2D6 allele found in Asians while its frequency in Caucasians and Africans is less than 10% (3, 10).
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