In the 1980’s, the cytochrome p450 (CYP) genes were identified and researched extensively. These are genes that encode enzymes which have been called a “superfamily of microsomal drug metabolizing enzymes”. Cytochrome P450 represents a family of isozymes responsible for biotransformation of many drugs via oxidation. The enzymes are heme-containing membrane proteins, which are located in the smooth endoplasmic reticulum of several tissues. Although a majority of the isozymes are located in the liver, extrahepatic metabolism also occurs in the kidneys, skin, gastrointestinal tract, and lungs. There are as many as 57 different CYP genes, but among these genes there are three families of genes (CYP1, CYP2, and CYP3) that are the most important in the oxidative metabolism of drugs. CYP families are classified based on pairwise amino acid sequence identity between individual members. Families CYP 1-3 are involved in phase I metabolism of human drugs and xenobiotic compounds, whereas other CYP families (CYP 4, 11, 17, and 21) are involved in the metabolism of endogenous compounds such as fatty acids, steroids, eicosanoids, bile acids and fat soluble vitamins.
From bacteria to humans, the functional breadth of cytochrome P450 activity is far ranging. At the latest count there were significantly more than 2000 identified cytochrome P450 genomic and cDNA sequences that have been divided into a total of 265 different families. Cytochromes P450 appear in every kingdom from bacteria to higher eukaryotes. Multiple cytochrome P450 genes can be expressed simultaneously as different isozymes and the number of genes per species is highly variable with a tendency for higher eukaryotes to possess more. The cytochromes P450 constitute the major enzyme family capable of catalyzing the oxidative biotransformation of most drugs and other lipophilic xenobiotics and are therefore of particular relevance for clinical pharmacology. The central role that these ubiquitous proteins play as phase I enzymes in human drug metabolism makes them very important to the pharmaceutical industry.
The studies of CYP genes have led to the discovery of many different polymorphisms in the population. These polymorphisms are generally defined as variant alleles that occur in the population at a certain frequency, usually greater than 1%. Some of these polymorphisms, or variations in DNA sequence, can lead to changes in CYP enzyme activity. These changes can include a decrease, increase, or even negation of the enzymatic activity. These polymorphisms can then be used to classify patients with respect to their drug metabolizing phenotypes. Patients with two alleles that encode for enzymes with normal function are classified as extensive metabolizers (EM) which is the “normal” or wild-type classification. Patients with two alleles that code for inactive or absent enzyme are classified aspoor metabolizers (PM). Generally, patients with alleles that code for one active and one inactive enzyme are classified as intermediate metabolizers (IM) or heterozygous EM. It’s also possible to have enzymes with increased activity or duplication of the CYP genes. Patients with these polymorphisms are classified as ultrarapid metabolizers (UM). Once the patient has been classified based on their CYP genotype, understanding the clinical impact of the classification is crucial.
Miller, Ryan T.Physician Views of Cytochrome P450 Genotyping and Pharmacogenetics. Mount Sinai School of Medicine of New York University, 2007.
Siegle, Daniel.Cytochrome P450 Inhibitor Classification with Statistical Learning. Diss. North Carolina Central University, 2015.
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