Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism PDF

Preface

This book focuses on how genetic, epigenetic, physiological, pathological, and structural factors govern the highly variable metabolism of a number of drugs in clinical use by human cytochrome P450 2D6 (CYP2D6), an important enzyme in the liver. The book covers in depth our current knowledge about the structure, function, polymorphism, and regulation of CYP2D6. It highlights the functional consequences and relevance of the structural and polymorphic changes of CYP2D6, the impact on clinical practice and drug development, and implications in precise medicine.

The human CYP superfamily contains 57 functional genes and 58 pseudogenes within 14 subfamilies. Four families of CYPs, CYP1, CYP2, CYP3, and CYP4, are the main ones contributing to the oxidative metabolism of more than 95% of clinical drugs, with CYPs in other families mainly being involved in the metabolism of important endogenous compounds such as steroids, fatty acids, retinoids, and arachidonic acids. CYP2D6, the focus of this book, accounts for only a small percentage of total hepatic CYP content (~2%–4%). However, it metabolizes ~25% of all medications and more than 160 drugs in the human liver. CYP2D6 is highly polymorphic and subject to inhibition by a number of drugs, therefore resulting in a large interindividual variability in drug clearance and response, possibly the occurrence of adverse drug reactions, and harmful drug–drug interactions. Notably, this enzyme is not induced by all known conventional CYP inducers, although a genome-wide association study indicated that more than 1600 genes can regulate the expression of CYP2D6 in humans.

This book consists of eight chapters that cover an overview of the human CYP superfamily, mammalian CYP2D members, substrate specificity of CYP2D6, inhibitor selectivity of CYP2D6, structural features of CYP2D6, regulation of CYP2D6, and pharmacogenomics of CYP2D6. It is unique because it is the first book that addresses a single but important CYP enzyme in detail, including its structure, function, regulation, and polymorphism that plays a very important role in individualized pharmacotherapy, drug development, and toxicology. This book will be useful for clinicians, pharmacists, pharmaceutical scientists, pharmacologists, geneticists, and toxicologists. It tells us how important this enzyme is and how we can use drugs more reasonably and safely. Since the book has updated knowledge about this single enzyme, it can be used as an important reference book by medical, pharmacy, biomedical, pharmaceutical, and nursing students. The book is also a good source of knowledge about CYP2D6 for public, private, and university libraries.

I acknowledge my appreciation for the great support from my wife Judy Liang, my daughter Helen Chew, and my son Kevin Chow. I also appreciate the support from Dr. Judy L. Genshaft, Professor Charles (Charly) J. Lockwood, Professor Kevin B. Sneed, Professor Howard L. McLeod, Professor Guangji Wang, Professor Lin He, Professor Kaitai Yao, Professor Kaixian Chen, Professor Yixin Zeng, Professor Mark S. Kindy, Professor Zhixu He, Professor Tianxin Yang, Professor Wei Duan, Professor William T. Beck, Professor Yinxue Yang, Professor Zhi-Min Yuan, Professor Xiaowu Chen, Professor Xueji Zhang, Professor Shuming He, Professor Jiaxuan Qiu, Professor Eric B. Haura, Professor Min Huang, and Professor Penghui Zhou. In addition, I appreciate the technical support from Dr. Zhi-Wei Zhou, Cameron T. Durlacher, Christopher J. Menzie, and Tommy Rogers. I hope that this book will become a good resource to advocate further studies on human CYP2D6 with regard to its regulation and the functional impacts of its polymorphisms.