Cytochrome P450 enzymes: Significance, multiplicity of isoforms, substrates, catalytic and regulatory mechanisms, physiological functions and clinical correlations

Historically there has been considerable interest in com paring patterns of biotransformation of xenobiotic chemicals in experimental animal models an d humans, e.g. in areas such as drug metabolism and chemical carcinogenesis . With the availability of more basic knowledge it has become possible to a ttribute the oxidation of selected chemicals to individual cytochrome P450 enzymes in animals and humans. Further, these cytochrome P450 enzymes can b e characterized by their classification into distinct subfamilies, which ar e defined as having >59% amino acid sequence homology. The cytochrome P450 (P450) enzymes are present throughout most of the phylogenetic spectrum. P4 50s are involved in the oxidation of other com pounds normally found in ver tebrates or 'endobiotics', e.g. fat-soluble vitamins, fatty acids, eicosano ids, and even alkaloids. However, most of the liver microsomal P450s oxidiz e a wide variety of substrates and have the function of removing natural pr oducts (ingested in food-stuff) from the body. In support of this view, the levels of many of these P450s vary dramatically among humans, as opposed t o the levels of steroidogenic P450s, which are tightly regulated. Cytochrom e P450s also function in critical roles in the synthesis of some steroids, and loss of function can be debilitating or lethal. Well over 500 P450s hav e now been characterized at the level of their DNA sequences. Quoting this number is somewhat misleading, because the number of P450s in a single spec ies is probably no higher than 40-50, at least at our current state of know ledge. The 'total' number of cytochrome P450s will probably grow very large with more information about P450s in insects, plants, bacteria and vertebr ate species that have not yet been examined in detail.