Cytochrome P450 Part 1: Multiplicity and Function

While new cytochrome P450 (CYP450) enzymes continue to be identified, it is now possible to predict with some confidence the total number of human CYP450 enzymes. This review is an update of the CYP450 superfamily of drug metabolising enzymes. It comprises a brief history of CYP450 research, outlines the standard P450 nomenclature system, and describes CYP450 multiplicity, structure and function. J Pharm Pract Res 2008; 38: 55-7. INTRODUCTION Cytochrome P450 (CYP450) is the generic name given to a large family of versatile enzymes that metabolise most drugs and a myriad of chemicals of toxicological importance (termed xenobiotic metabolism). Along with xenobiotic metabolism, many CYP450 enzymes play pivotal roles in diverse physiological processes including steroid and cholesterol biosynthesis, fatty acid metabolism (prostacyclin, thromboxane) and the maintenance of calcium homoeostasis. Mutations in CYP450 genes or deficiencies in CYP450 enzymes are clinically relevant in many instances, with the consequences dependent on the function of the compromised enzyme. Advances in recombinant DNA technology have provided extensive insights into the multiplicity and function of CYP450 enzymes from many different species including humans. While new CYP450 enzymes continue to be identified, it is now possible to predict with some confidence the total number of human CYP450 enzymes. This review comprises a brief history of the CYP450 enzymes, outlines the standard P450 nomenclature system, and describes CYP450 multiplicity, structure and function. Subsequent articles in this series will focus on the pharmacogenetics of these cytochromes and clinically important drug interactions involving CYP450 enzymes. HISTORY The term ‘cytochrome P450’ was coined in 1962 as a temporary name for a coloured substance in the cell. This pigment, when reduced and bound with carbon monoxide, produced an unusual absorption peak at a wavelength of 450 nm. Cytochrome is a misnomer given that the CYP450s are enzymes rather than true cytochromes. Despite this, the name ‘cytochrome P450’ has stuck and is so widely accepted that any change would be impractical. At first, CYP450 was believed to represent a single enzyme. Today it seems likely that humans and other mammals have approximately 50 distinct CYP450 enzymes. The total number may be higher in plants, possibly as high as several hundred. In the last 15 years of the 20th century, research was largely concerned with defining CYP450 multiplicity in humans and a diverse range of other organisms. In recent years, with CYP450 multiplicity largely covered, CYP450 functional and structural studies have taken precedence. NOMENCLATURE AND MULTIPLICITY Initial evidence for CYP450 multiplicity came via enzyme purification but recombinant DNA technology enabled the recognition of the considerable enzyme multiplicity within the CYP450 system. As individual CYP450s were identified in various laboratories, several diverse CYP450 nomenclature systems emerged based on their molecular weights or preferences for substrates. The resultant plethora of names and accompanying confusion prompted prominent workers in the field to devise a standard nomenclature for the CYP450 gene family based on amino acid sequence comparisons and the evolutionary relationships of the corresponding genes. First proposed in 1987, the nomenclature was devised with the premise that it would be updated as frequently as the identification of new CYP450 enzymes necessitated. Several updates of the CYP450 gene superfamily have been published. In addition, an official web site has been established, based at the University of Memphis, to provide up-to-date information concerning CYP450 multiplicity in all species. Nomenclature Recommendations for naming a CYP450 gene include: • the root symbol CYP for cytochrome P450; • an Arabic number for the CYP450 family; • a letter for the subfamily; and • an Arabic numeral for the individual gene. When describing a CYP450 gene, all letters and numerals are written in italics. The same nomenclature is recommended for the enzyme but it is written in nonitalicised form. Thus, the CYP2D6 gene encodes the CYP2D6 enzyme. Although the distinctions between CYP450 families and subfamilies are arbitrary, it is estimated that CYP450 families diverged from one another more than 1.2 billion years ago, so any enzyme in one CYP450 family is less than 40% similar, at the amino acid level, to a CYP450 from another family (e.g. CYP2D6 and CYP3A4 are less than 40% similar, CYP2D6 and CYP2C19 are more than 40% similar). The subfamilies are estimated to have diverged from one another approximately 400 million years ago. Any two CYP450 enzymes within a single mammalian CYP450 subfamily generally have more than 55% amino acid similarity (e.g. CYP2C9 and CYP2C19 are more than 55% similar). It must be stressed that the nomenclature system is based on evolutionary relationships between CYP450 enzymes and not on similarity in substrate profiles. Indeed some CYP450 enzymes from within a single family display markedly different substrate profiles and/or physiological function. Nomenclature systems based on the substrate profiles of individual CYP450s are of little use given the overlapping substrate profiles of CYP450s and the capacity of multiple CYP450s to modify a single drug at different sites. The success of the CYP450 nomenclature based on evolutionary