Cytochrome P450
A Wealth
of Enzymes
In mammals, CYP enzymes can oxidise a variety of different substrates, including steroids, fatty acids and xenobiotics. Of the thousands of CYP proteins identified, 58 have been found in humans alone. Individual CYP proteins follow the nomenclature: CYP, followed by a number (family), then a letter (subfamily), and another number (protein); e.g. CYP3A4 is the fourth protein in family 3, subfamily A. The different CYP enzymes have different substrate specificities, and are often restricted to specific cell types as well. For example, CYP2J2 is involved in arachidonic acid metabolism and is primarily expressed in the heart, while CYP2D6 is involved in the degradation of xenobiotics such as codeine, and is primarily expressed in the liver.
Alternative splicing
Alternative splicing has been found to occur with many CYP proteins, which further increases their genetic diversity and may be involved in the regulation of transcription of certain CYP proteins. Some of these splice-variants are tissue-specific. In addition to alternative splicing, tissue-specific gene promoters allow greater versatility in the regulation of CYP proteins within specific tissues.
Fusion Enzymes
Some CYP proteins have been found to exist as fused domains with one or more of their redox partners, which can have the evolutionary advantage of increasing catalytic efficiency. Fusion proteins have been found in both prokaryotic and eukaryotic systems, with a wide variety of cytochrome P450/redox partner fusions. For example, in B. megaterium, soluble cytochrome P450 is covalently linked to a reductase enzyme to produce a highly efficient system for the oxygenation of fatty acids. In another bacterial system, CYP has been found attached as an N-terminal domain to a phthalate dioxygenase reductase module, which allows the reductase to facilitate the breakdown and metabolism of aromatic phthalate.
Polymorphic variations
People can carry different alleles of CYP genes, these alleles having a slight variation in their genetic sequence due to nucleotide changes, or polymorphisms. These polymorphic variations can result in individual and population differences in the tolerance to toxins and drugs. Because CYP proteins are specific in terms of which drugs they clear and which they activate, polymorphic variations in different CYP genes can have different effects. Furthermore, whether the gene is rendered more active or less active can have opposing effects.
For example, CYP2D6 is expressed at high levels in many people from Saudi Arabia and Ethiopia. CYP2D6 can degrade and clear several drugs, including anti-depressants and neuroleptics, making them ineffective if the level of CYP2D6 is too high. In addition, CYP2D6 can turn other drugs into active metabolites, such as converting codeine into the more potent morphine, which can reach dangerous levels in people with elevated CYP2D6 levels. By contrast, people deficient in CYP2D6 will have the reverse effects, namely a predisposition to drug toxicity when taking anti-depressants and neuroleptics (which are not broken down efficiently if CYP2D6 is absent), while finding codeine ineffective.