Cytochromes P450: Role in the Metabolism and Toxicity of Drugs and other Xenobiotics
During half a century, cytochrome P450 in its original uniqueness as an optically "wrong" cytochrome has attracted many investigators, who have contributed to the unveiling of a bewildering multiplicity of biologically important functions of the, by now very large, superfamily of cytochrome P 450 enzymes. With its discovery in 1958 and with the advent of more refined spectroscopic methodologies, through the double wavelength spectrophotometry, the mysterious enzyme system began to reveal its secrets in a swift stream of investigative successes. As one of the most extensively studied enzyme systems worldwide the interest in cytochromes P450 very much reflects its importance in the elimination of drugs and other chemicals from the body and its role in chemical toxicity and in the aetiology of diseases such as cancer. There has been significant progress in research in this area in recent years and current books on this subject are now out of date. This much needed, new, fully up-to-date publication fills this gap and emphasises the new relevant topics that have emerged during the last decade in an easily accessible manner. The enzyme system, cytochromes P450, comprises a number of families/subfamilies, and the focus of the book is to deal with each individually, furnishing information directly relevant to scientists involved in the development of chemicals, in particular in the evaluation of their safety. The book has contributions from internationally respected scientists who are research-active in the relevant areas. The authors have made extensive use of figures and tables so that the reader can access the necessary information without always having to read the text. In addition, a very extensive, user-friendly index is a unique hallmark of the book. Part A of this monograph introduces the reader to the current knowledge of the evolutionary development of cytochrome P450 structure and function. Furthermore, it deals with the role of this enzyme in the formation of reactive intermediates. The shrewd and extensive utilisation of the molecular biology methodology very rapidly led to a vast body of enzymes calling for a classification of the plethora of different cytochromes P450 (the superfamily) into families and subfamilies. This is aptly exemplified by the ten chapters in Part B of this book, dealing with ten subfamilies and two families of cytochrome P450. Part C offers an insight into another aspect of cytochrome P450 research, namely its regulation through receptor-mediated stimuli - as opposed to enzyme induction or inhibition. The final chapter translates the current data on one of several drug metabolising systems into clinical application and highlights the role of cytochromes P450 in the treatment of neoplastic growth. The book deals extensively with each family/subfamily of the cytochromes P450 that contribute to the metabolism of xenobiotics. Essential and invaluable information is provided for the industrial research scientist working with fine chemicals, and especially those in the pharmaceutical industry, dealing with the safety evaluation of chemicals or being involved in the study of their metabolism, pharmacokinetics and toxicological properties. It should also prove of interest to Regulators concerned with the safety evaluation of chemicals, research pharmacologists and toxicologists, and postgraduate students studying drug metabolism and toxicology at an advanced level.