Cytochrome P450 Enzymes
Cytochrome p450 is a family of heme-containing enzymes that catalyze the conversion of lipophilic substances into hydrophilic molecules which can then be excreted by kidneys into the urine.
It represents a major part of the body’s powerful detoxification systems.
The cytochrome p450 system metabolizes endogenous and exogenous substrates through a variety of reactions including epoxidation, N-dealkylation, O-dealkylation, S-oxidation, and hydroxylation. Exogenous substances (products ingested or absorbed) include not only pharmaceutical compounds given as therapeutic drugs, but also foodstuffs and dietary components, and occupational pollutants and industrial chemicals.
The cytochrome p450 mixed-function mono-oxygenase system is probably the most important element of phase I metabolism in mammals. More than half of all drugs are primarily cleared by the cytochrome p450 system.
As a group, these enzymes are often referred to as drug-metabolizing enzymes (DME). The activity of these enzymes is modulated by a variety of factors including age, diet, concomitant medications as well as genetic variability.
The cytochrome p450 system has evolved into a gene family and expanded into multiple chromosome loci, each with tandem arrays of genes, and each gene with substantial polymorphism. This system is an illustration of gene expansion, multi-gene families, and allelic functional variation. Genomics has supplied a rich resource of gene mapping data as well as the individual variants in each gene at the single nucleotide polymorphism (SNP) and chromosome locus levels.
The 57 cytochrome p450 isoforms now known in humans, along with the hundreds of genetic variations, have produced a large set of biomarkers predictive of susceptibility to specific toxins.
The fact that the pharmaceutical industry routinely includes an assessment of the main metabolic pathways of a candidate drug to derive clinical pharmacological correlations is indicative of the importance of this knowledge.
In addition, certain cytochrome p450 alleles can also be disease susceptibility markers. For example, some are known to be implicated in detoxification or activation of environmental toxins and variants associated with cancer risk.
The nomenclature used to categorize the variant alleles of the cytochrome p450 enzyme system has been defined by various organizations. In general, the descriptors rely on the hierarchy of the genetic structures involved in the construction of the enzymes.
Of the cytochrome P450 enzymes described to date and most closely related to clinical applications through pharmacogenetic testing are the CYP2D6, CYP2C9, and CYP2C19 enzymes.
Factors such as the high prevalence of variants, and in the case of CYP2D6 full-length gene duplications, in human populations and wide range of therapeutics metabolized by these enzymes render them among the most relevant drug metabolizing enzyme for PGx diagnostics.