Cytochromes P450 Cyp Ec 114141 Multiplicity of CYPs2,4-8 The nomenclature of the multiple CYPs is described elsewhere in this book (see 5.05 Principles of Drug Metabolism 1: Redox Reactions). When attempting to extrapolate toxicological results obtained in an experimental animal species to human it is often helpful to discriminate whether orthologous CYPs exist in the test species and in man since in many cases, apart from the conservation of a high percentage of the overall primary structure, much of the individual function including substrate specificity is conserved among species in orthologous enzymes. It is possible to define orthologous enzymes in different organisms if there is higher sequence similarity between these forms from different species than there is between the closely related isoenzymes of the same subfamily within the same species. Such orthologous CYPs from different species receive the same designation. This is the case for the individual isoenzymes of CYP family 1. If the assignment of orthologous CYPs is not possible the CYPs within the subfamily are numbered consecutively (many CYPs from families 2, 3, and 4).1 Enzymatic mechanism of the reactions catalyzed by CYP and toxicological consequences The CYP-catalyzed oxygenation proceeds by a number of sequential steps forming the CYP reaction cycle (Figure 2; see 5.05 Principles of Drug Metabolism 1: Redox Reactions).2'5'6 The prosthetic heme of CYP has its central iron in the ferric state [Fe3 + ] and, in most CYPs, is predominantly low spin in its d5-orbitals. Binding of a substrate in the catalytic pocket of CYP in most cases leads to the conversion of the iron from the low- to the high-spin configuration, which favors the reduction of the ferric [Fe3 + ] to the ferrous [Fe2 + ] iron of CYP by the NADPH-CYP-reductase by a one-electron transfer. In this state, the iron can bind molecular oxygen to form a Fe2 + -O2 complex. The generation of the ultimately activated form of oxygen is now initiated by a further reduction, again by a one-electron transfer. This is

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