Characterization Of Interindividual Variability And Differential Tissue Abundance Of Ugt2b17

UGT2B17 is an androgen- and drug-conjugating enzyme with a remarkably high interindividual variability in its hepatic protein expression. Testosterone is one of its main endogenous substrates, and various clinical associations between UGT2B17 and testosterone-related and other pathophysiological outcomes have been reported, along with associations with drug and xenobiotic disposition. UGT2B17 also exhibits relatively high and variable intestinal abundance, compared to the liver, both in absolute abundance and relative to other UGT isoforms, which brings in concern for first pass metabolism and differential drug-drug interactions. Multiple factors, including a common copy number variation (CNV), sex, age, and certain SNPs, contribute to UGT2B17 tissue abundance variability, but only account for a small portion of that variability. Unexplained interindividual differences in UGT2B17 tissue abundance, along with UGT2B17's unique ontogeny, highlights the need for a phenotypic biomarker to assess in vivo UGT2B17 activity. This dissertation project focuses on characterizing interindividual variability and differential tissue abundance of UGT2B17. Chapter 2 explores UGT2B17's role in first pass metabolism of testosterone in human in vitro models for the small intestine and liver and explores its role in the disposition of orally administered testosterone. Findings confirm that UGT2B17 drives testosterone glucuronide (TG) formation in liver and intestine, and the higher intestinal abundance may explain oral testosterone's high and variable first pass metabolism and low bioavailability. In Chapter 3, urinary TG normalized with androsterone glucuronide (TG/AG) is identified as a potential urinary biomarker for UGT2B17 and validated in longitudinal urine samples from 63 pediatric subjects. Significant associations between TG/AG and sex, age, and UGT2B17 CNV were found. Chapter 4 investigates regional enzyme abundance of UGT2B17 and non-CYP enzymes in cryopreserved human intestinal mucosa (CHIM), corroborates proteomic findings with activity assays, and proposes enterocyte marker proteins as normalizers to control for intestinal tissue heterogeneity. Non-CYP enzymes that were quantifiable were carboxylesterase 1 (CES1), CES2, UGT1A1, UGT1A3, UGT1A10, UGT2B7, UGT2B17, sulfotransferase 1A1 (SULT1A1), SULT1A3, SULT1B1, and SULT2A1. We also found good enzyme abundance-activity correlations, demonstrating that CHIMs are functionally active with respect to xenobiotic metabolism. This dissertation improves the understanding of UGT2B17's role in first pass drug metabolism and potential drug-drug interactions. It also establishes a promising phenotypic urinary biomarker for UGT2B17 for further applications in drug development and disease state associations.

Identification and Quantification of Drugs, Metabolites, Drug Metabolizing Enzymes, and Transporters, Second Edition, is completely updated to provide an overview of the last decade’s numerous advances in analytical technologies for detection and quantification of drugs, metabolites, and biomarkers. This new edition goes beyond LC-MS and features all-new chapters on how to evaluate drug absorption, distribution, metabolism, and excretion, potential for hepatic and renal toxicity, immunogenicity of biotherapeutics and translational tools for predicting human dosage, safety and efficacy of small molecules and biologics. This book will be an important handbook and desk reference for pharmacologists, toxicologists, clinical scientists, and students interested in the fields of pharmacology, biochemistry, and drug metabolism. Four sections in the book with 24 chapters give readers an overview of state-of-the-art techniques for identifying and quantifying drugs, metabolites and biomarkers, including a chapter on new approaches for quantification of enzymes and transporters in different tissues Focuses on the role of drug metabolism enzymes, transporters in disposition and drug-drug interactions, as well as strategies for evaluating drug metabolism and safety using advanced liver and kidney models. Discussions on immunogenicity risks of biologics and their evaluation methods have been included Includes several chapters on advanced translational sciences to predict human dosage, pharmacokinetics and efficacy for small molecules and biotherapeutics All chapters are written by experts with a wide range of practical experience from the industry and academia

This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

Identification and Quantification of Drugs, Metabolites, Drug Metabolizing Enzymes, and Transporters, Second Edition, is completely updated to provide an overview of the last decade's numerous advances in analytical technologies for detection and quantification of drugs, metabolites, and biomarkers. This new edition goes beyond LC-MS and features all-new chapters on how to evaluate drug absorption, distribution, metabolism, and excretion, potential for hepatic and renal toxicity, immunogenicity of biotherapeutics and translational tools for predicting human dosage, safety and efficacy of small molecules and biologics. This book will be an important handbook and desk reference for pharmacologists, toxicologists, clinical scientists, and students interested in the fields of pharmacology, biochemistry, and drug metabolism. Four sections in the book with 24 chapters give readers an overview of state-of-the-art techniques for identifying and quantifying drugs, metabolites and biomarkers, including a chapter on new approaches for quantification of enzymes and transporters in different tissues Focuses on the role of drug metabolism enzymes, transporters in disposition and drug-drug interactions, as well as strategies for evaluating drug metabolism and safety using advanced liver and kidney models. Discussions on immunogenicity risks of biologics and their evaluation methods have been included Includes several chapters on advanced translational sciences to predict human dosage, pharmacokinetics and efficacy for small molecules and biotherapeutics All chapters are written by experts with a wide range of practical experience from the industry and academia

This ambitious and comprehensive handbook represents an essential contribution to our current understanding of interactions between heart and brain, a research topic generating growing interest. Despite the increasing awareness that neural mechanisms are the primary cause of cardiac disease and its progression, therapy continues to focus on end-organ protection and does not approach the neural core of the problem. Growing public health problems such as heart failure are still treated with autonomic drugs that are 30-40 years old and simply act on cardiac receptors. However, it has now been shown that the progression of ischemic heart disease to heart failure is mainly due to abnormal central responses to incipient cardiac disease, with neural activation the primary cause rather than the consequence of cardiac remodeling. Written by leading international experts in their respective research areas, the book presents a variety of perspectives on the core topic: from social and philosophical to gender-related aspects. It is designed for a broad readership and includes dedicated sections for cardiologists, psychiatrists, neurologists and psychotherapists looking for a more insightful and targeted approach to neuro-cardiovascular disease.

The objective of this Genetic Polymorphisms book is to rehighlight and provide few updates on the role of genetic polymorphisms in medicine and agriculture, which void emerging opinion on "full death" of genetic polymorphisms as useful genetic markers. Chapters presented here demonstrate the future benefit of SNPs in many genetic studies as well as prognosis disease and diagnosis.

Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes. Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

Toxicoepigenetics: Core Principles and Applications examines the core aspects of epigenetics, including chromatin biology, DNA methylation, and non-coding RNA, as well as fundamental techniques and considerations for studying each of these mechanisms of epigenetic regulation. Although its integration into the field of toxicology is in its infancy, epigenetics have taken center stage in the study of diseases such as cancer, diabetes, and neurodegeneration. Increasing the presence of epigenetics in toxicological research allows for a more in-depth understanding of important aspects of toxicology such as the role of the environment and lifestyle influencing the individual susceptibility to these effects and the trans-generational transmission of these health effects and susceptibilities. Methods chapters are included to help improve efficacy and efficiency of protocols in both the laboratory and the classroom. Toxicoepigenetics: Core Principles and Applications is an essential book for researchers and academics using epigenetics in toxicology research and study. Introduces the fundamental principles and practices for understanding the role of the epigenome in toxicology Presents the foundation of epigenetics for toxicologists with a broad range of backgrounds Discusses the incorporation of epigenetics and epigenomics into current toxicological studies and interpretation of epigenetic data in toxicological applications

Drug metabolism and transport are very important facets within the discipline of pharmaceutical sciences, with enzyme kinetic concepts utilized regularly in characterizing and modeling the disposition and elimination of drugs. Enzyme Kinetics in Drug Metabolism: Fundamentals and Applications focuses on very practical aspects of applying kinetic principles to drug metabolizing enzymes and transporters. Divided into five convenient sections, topics include the fundamental principles of enzyme kinetics, the kinetics of oxidative and conjugative drug metabolizing enzymes and drug transporters, modeling approaches for both drug metabolizing enzymes and transporters including novel systems biology approaches, understanding of variability both experimental and interindividual (pharmacogenomic), and case studies that provide real life examples of applying these principles. Written in the successful Methods in Molecular Biology series format, chapters include introductions to their respective topics especially suitable for the novice, in some cases step-by-step, readily reproducible protocols, and insights to help with troubleshooting and avoiding known pitfalls with extensive cross referencing to assist in learning. Authoritative and easily accessible, Enzyme Kinetics in Drug Metabolism: Fundamentals and Applications serves as a very practical teaching tool for novice, non-mathematically trained scientists interested in these fundamental concepts and as an aid for their supervisors in teaching these principles.

It is increasingly recognized that various transporter proteins are expressed throughout the body and determine absorption, tissue distribution, biliary and renal elimination of endogenous compounds and drugs and drug effects. This book will give an overview on the transporter families which are most important for drug therapy. Most chapters will focus on one transporter family highlighting tissue expression, substrates, inhibitors, knock-out mouse models and clinical studies.