Concise review of the cytochrome P450s and their roles in toxicology

The cytochrome P450s are hemoproteins that play critical roles in the bioactivation and detoxication of a wide variety of xenobiotic substances. The enzymes are encoded by a superfamily of genes. The term “cytochrome P450” originates from the observation that the reduced state of the proteins form complexes with carbon monoxide that exhibit absorbance maxima at 450 nm (Omura and Sato, 1964). The P450 enzymes are now referred to as heme-thiolate proteins. P450s have been characterized in many species of organisms, including bacteria, fungi, plants, fish, and mammalian systems (Nebert and McKinnon, 1994). In mammalian cells, P450s are localized predominantly in the smooth endoplasmic reticulum of the cell and are entirely distinct from the cytochrome proteins that comprise the mitochondrial electron-transport function. Currently, .700 P450s have been characterized, inclusive of the many different species of organisms that have been studied (Nelson et al., 1996). Based primarily on sequence similarities, a standardized nomenclature has been adopted that categorizes the individual P450s into respective families and subfamilies. P450 proteins exhibiting .40% similarity in protein sequence are classified within the same family; proteins exhibiting .55% sequence similarity are grouped into the same subfamily (Nebert and McKinnon, 1994; Nelson et al., 1996). Although the catalog is updated regularly, the current P450 nomenclature and classification scheme was most recently reviewed in 1996 (Nelson et al., 1996). The purpose of this current review is to very briefly highlight some of the more important mammalian P450s with respect to their expression, inducibility and inhibition character, and substrate preferences, especially as they relate to human toxicology. Due to this limited scope, it is impossible to thoroughly reference all the important and relevant literature pertaining to this topic. The reader is referred to other recent reviews for more detailed information (Dogra et al., 1998; Meyer and Zanger, 1997; Pelkonen and Raunio, 1997; Rendic and Di-Carlo, 1997). Information from these and other references has been used as source material to compile the contents of Table 1, summarizing some of the salient features of several relevant P450s.