Cytochrome P450 Enzymes : Significance, Multiplicity of Isoforms, Substrates, Catalytic and Regulatory Mechanisms, Physiological Functions and Clinical Correlation

Dr. B. R. Ambedkar Center for Biomedical Research Department of Chemistry, University of Delhi, Delhi-110 007 Manuscript received 14 September 1998 Historically there has been considerable interest in comparing patterns of biotransformation of xenobiotic chemicals in experimental animal models and humans, e.g. in areas such as drug metabolism and chemical carcinogenesis. With the availability of more basic knowledge it has become possible to attribute the oxidation of selected chemicals to individual cytochrome P450 enzymes in animals and humans. Further, these cytochrome P450 enzymes can be characterized by their classification into distinct subfamilies, which are defined as having >59% amino acid sequence homology. The cytochrome P450 (P450) enzymes are present throughout most of the pbylogenetic spectrum. P450s are involved in the oxidation of other compounds normally found in vertebrates or 'endobiotics', e.g. fat-soluble vitamins, fatty acids, eicosanoids, and even alkaloids. However, most of the liver microsomal P450s oxidize a wide variety of substrates and have the function of removing natural products (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 to the levels of steroidogenic P450s, which are tightly regulated. Cytochrome 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 have now been characterized at the level of their DNA sequences. Quoting this number is somewhat misleading, because the number of P450s in a single species is probably no higher than 40-50, at least at our current state of knowledge. The 'total' number of cytochrome P450s will probably grow very large with more information about P450s in insects, plants, bacteria and vertebrate species that have not yet been examined in detail