Ppars, Rxrs, and Drug-Metabolizing Enzymes
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PPAR Research PPARs, RXRs, and Drug-Metabolizing Enzymes Guest Editors: James P. Hardwick and John Y. L. Chiang PPARs, RXRs, and Drug-Metabolizing Enzymes Copyright © 2009 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in volume 2009 of “PPAR Researsh.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editor-in-Chief Mostafa Z. Badr, University of Missouri-Kansas City, USA Advisory Editors Yaacov Barak, USA Francine M. Gregoire, Singapore Michael K. Racke, USA Abdulbari B. Bener, Qatar Sander Kersten, The Netherlands Janardan K. Reddy, USA David Bishop-Bailey, UK Beata Lecka-Czernik, USA B. Staels, France George L. Blackburn, USA Christos S. Mantzoros, USA Theodore J. Standiford, USA Pierre Chambon, France Jorg¨ Mey, Germany Xian Wang, China V. Chatterjee, UK Laszlo Nagy, Hungary Jihan Youssef, USA Salvatore Cuzzocrea, Italy Takashi Osumi, Japan Jeffrey M. Gimble, USA Daniele Piomelli, USA Associate Editors Josep Bassaganya-Riera, USA Weimin He, USA Jeffrey M. Peters, USA Sandra Brunelleschi, Italy Jaou-Chen Huang, USA Richard P. Phipps, USA Antonio Brunetti, Italy Norio Ishida, Japan Suofu Qin, USA Agustin Casimiro-Garcia, USA Fredrik Karpe, UK Michael E. Robbins, USA Ching-Shih Chen, USA Shigeaki Kato, Japan Ruth Roberts, UK Hyae Gyeong Cheon, South Korea Ulrich Kintscher, Germany Sarah J. Roberts-Thomson, Australia Sharon Cresci, USA Joshua K. Ko, China Lawrence Serfaty, France Michael L. Cunningham, USA Carolyn M. Komar, USA Muhammad Y. Sheikh, USA Samir Deeb, USA Christopher Lau, USA Xu Shen, China Beatrice´ Desvergne, Switzerland Chih-Hao Lee, USA Xing-Ming Shi, USA Paul D. Drew, USA Todd Leff,USA Alexander Staruschenko, USA Klaus Eder, Germany Harry Martin, New Zealand Eiji Takeda, Japan Douglas Feinstein, USA Anne Reifel Miller, USA Michal Toborek, USA Ana Z. Fernandez, Venezuela Raghavendra G. Mirmira, USA Anna Tsantili-Kakoulidou, Greece Brian N. Finck, USA Hiroyuki Miyachi, Japan Raghu Vemuganti, USA Pascal Froment, France Kiyoto Motojima, Japan Nanping Wang, China Howard P. Glauert, USA Shaker A. Mousa, USA Barbour S. Warren, USA Gregory Graf, USA Elisabetta Mueller, USA Wei Xu, USA Youfei Fei Guan, China Marcelo Napimoga, Brazil Tianxin Yang, USA James P. Hardwick, USA Dipak Panigrahy, USA Contents PPARs, RXRs, and Drug-Metabolizing Enzymes, James P. Hardwick and John Y. L. Chiang Volume 2009, Article ID 589626, 2 pages Peroxisome Proliferator-Activated Receptor and Retinoic X Receptor in Alcoholic Liver Disease, Tommaso Mello, Simone Polvani, and Andrea Galli Volume 2009, Article ID 748174, 11 pages Regulation of Sulfotransferase and UDP-Glucuronosyltransferase Gene Expression by the PPARs, Melissa Runge-Morris and Thomas A. Kocarek Volume 2009, Article ID 728941, 14 pages Regulation of Bile Acid and Cholesterol Metabolism by PPARs, Tiangang Li and John Y. L. Chiang Volume 2009, Article ID 501739, 15 pages A Human Hepatocyte-Bearing Mouse: An Animal Model to Predict Drug Metabolism and Effectiveness in Humans, Katsutoshi Yoshizato and Chise Tateno Volume 2009, Article ID 476217, 11 pages PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid ?-Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease,JamesP.Hardwick, Douglas Osei-Hyiaman, Homer Wiland, Mohamed A. Abdelmegeed, and Byoung-Joon Song Volume 2009, Article ID 952734, 20 pages Hindawi Publishing Corporation PPAR Research Volume 2009, Article ID 589626, 2 pages doi:10.1155/2009/589626 Editorial PPARs, RXRs, and Drug-Metabolizing Enzymes James P. Hardwick and John Y. L. Chiang Department of Biochemistry and Molecular Pathology, Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy (NEOUCOM/NEOUCOP), 4209 State Route 44, Rootstown, OH 44272, USA Correspondence should be addressed to James P. Hardwick, [email protected] Received 23 September 2009; Accepted 23 September 2009 Copyright © 2009 J. P. Hardwick and J. Y. L. Chiang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This special issue of PPAR Research is dedicated to “PPARs, progression of alcoholic liver disease (ALD). A second review RXRs and Drug Metabolizing Enzymes”.Knowledge of PPAR focuses on the role of PPAR isoforms in the regulation of biology, over the past five years, has dramatically increased bile acid and cholesterol metabolism, with specific insight our understanding of the potential therapeutic usefulness into how PPARα regulates bile acid synthesis, conjugation, of these receptors in metabolic alterations associated with and transport by phase II and III enzymes. This review disease process of alcoholic and non-alcoholic fatty liver also provides an updated report on how PPARs regulate disease and metabolic syndrome. In addition, the utility of cholesterol synthesis, absorption, and reverse cholesterol PPAR agonist in the treatment of liver disease by normalizing transport, and how PPAR agonist may be used to treat hypertriglyceridemia, dyslipidemia, and the toxic effects of cholestatic liver disease. This review also raises important bile acids has a sound scientific basis in the ability of PPAR questions concerning the use of PPAR agonist in treating receptors to control lipid oxidation and disposal as well as bile acid accumulation in several liver diseases, which leads regulators of hepatic inflammation. Further insight into both to hepatocyte injury, impaired liver metabolic function, the indirect and direct effects of dual and pan PPAR agonist progressing to liver fibrosis and cirrhosis. Further research may potentiate the development of new therapeutic modal- needs to focus on how selective PPAR agonist and isoforms ities to treat fatty acid oxidation disorders, dyslipidemia, regulated bile acid conjugation and thereby prevent bile acid inflammation, and bile acid accumulation associated with toxicity observed in cholestastic disease. The conjugation of several liver diseases and metabolic syndrome. bile acids by UDP-glucuronosyltransferase, a PPAR target Articles included in this special issue highlight the imp- gene further emphasizes the importance of PPAR in bile ortance of PPARs and RXR in drug metabolism and hepatic acid toxicity. In addition, induction of the sulfotransferase diseases associated with metabolic disorders. Alterations in genes by PPAR and sulfonation of cholesterol in keratinocyte drug metabolizing gene expression in different disease sta- differentiation suggests that these phase II genes have tes due to the differential expression of PPAR isoforms hig- an important role in epidermal wound healing. Finally, hlights the importance of PPAR in disease progression although numerous studies in animal models of disease have and as therapeutic target in the amelioration of disease dramatically increased our understanding of how PPARs not progression. The first review summarizes past and new only regulate drug metabolism and the elimination of drugs developments in alcoholic fatty liver disease (ALD) and how and toxic endogenous metabolities in disease progression, PPAR/RXR regulates phase I enzymes in alcohol metabolism the application of these results to human in the design and the redox balance of cells. The direct impairment of effective PPAR agonist has all too often led to adverse of PPAR by acetaldehyde results in reduction of NAD+ drug interactions and unacceptable drug toxicity. A fourth pool leading to alterations in lipid metabolism, increased review in this series details the exciting possibility of using oxidative stress, and increased pro-inflammatory cytokines, a human hepatocyte chimeric mouse model to predict chemokines and acute phase proteins, which may be central metabolism and possible effectiveness of new PPAR agonist in the onset and perpetuation of mechanism in the clinical in humans. The investigators clearly show the utility of 2 PPAR Research this model system by the increased phosphatidylcholine transport into bile canaliculi through induction of human ABCB4 transporter by benzafibrate activation of PPAR. There are marked species differences in genes and proteins associated with the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics and drugs, thus the human hepatocyte chimeric mice may not only be used for increasing the safety and effectiveness of lead drugs, but may also serve as a model system to study human liver disease and assess the potency and efficacy of dual and pan PPAR agonist in preventing or delaying disease progression. The final review in these series details how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and explores how medium chain fatty acid (MCFA) CYP4A and long chain fatty acid (LCFA) CYP4F ω-hydroxylase genes are regulated in fatty liver. The authors propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may pro- mote the progression of steatosis to steatohepatitis. We thank the editors for the opportunity to share with other investigators these interesting reviews on drug metab- olizing genes regulated by PPAR/RXR. It is apparent that drug metabolizing genes not only play a pivotal role in drug efficacy, drug toxicity, and adverse