Molecular Aspects of Oxidative Drug Metabolizing Enzymes: Their Significance in Environmental Toxicology, Chemical Carcinogenesis and Health

Transcription

1 Molecular Aspects of Oxidative Drug Metabolizing Enzymes: Their Significance in Environmental Toxicology, Chemical Carcinogenesis and Health

2 NATO ASI Series Advanced Science Institutes Series A series presenting the results of activities sponsored by the NA TO Science Committee, which aims at the dissemination of advanced scientific and technological knowledge, with a view to strengthening links between scientific communities. The Series is published by an international board of publishers in conjunction with the NATO Scientific Affairs Division A Life Sciences B Physics C Mathematical and Physical Sciences D Behavioural and Social Sciences E Applied Sciences F Computer and Systems Sciences G Ecological Sciences H Cell Biology I Global Environmental Change Plenum Publishing Corporation London and New York Kluwer Academic Publishers Dordrecht. Boston and London Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest NATo-pea DATABASE The electronic index to the NATO ASI Series provides full bibliographical references (with keywords and/or abstracts) to more than contributions from international scientists published in all sections of the NATO ASI Series. Access to the NATO-PCO DATABASE compiled by the NATO Publication Coordination Office is possible in two ways: - via online FILE 128 (NATO-PCO DATABASE) hosted by ESBIN, Via Galileo Galilei Frascati. Italy. - via CD-ROM "NATO Science & Technology Disk" with user-friendly retrieval software in English, French and German ( WTV GmbH and DATAWARE Technologies Inc. 1992). The CD-ROM can be ordered through any member of the Board of Publishers or through NATO-PCO. Overijse. Belgium. Series H: Cell Biology, Vol. 90

3 Molecular Aspects of Oxidative Drug Metabolizing Enzymes: Their Significance in Environmental Toxicology, Chemical Carcinogenesis and Health Edited by EmelAnn<; Middle East Technical University, Department of Biology InonO Bulvan, Ankara 06531, Turkey John B. Schenkman University of Connecticut Health Center, Department of Toxicology Farmington, Connecticut 06032, USA Ernest Hodgson North Carolina State University, Department of Toxicology Raleigh, North Carolina 27695, USA Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest Published in cooperation with NATO Scientific Affairs Division

4 Proceedings of the NATO Advanced Study Institute on molecular aspects of drug metabolizing enzymes, held in Ku adasi, Aydin-Turkey, June 2O-July 2, 1993 Additional material to this bood can be downloaded from ISBN-13: e-isbn-13: : / CIP-data applied for This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights oftranslation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag Berlin Heidelberg 1995 Softcover reprint of the hardcover 1st edition 1995 Typesetting: Camera ready by authors SPIN / Printed on acid-free paper

5 Preface The second NATO Advanced Study Institute on molecular aspects of drug metabolizing enzymes, entitled Molecular Aspects of Oxidative Drug Metabolizing Enzymes: Their Significance in Environmental Toxicology, Chemical Carcinogenesis and Health was held in Ku~adasl, Aydm-Turkey, June 20-July 2, Like the first NATO Institute, Molecular Aspects of Monooxygenases and Bioactivation of Toxic Compounds, held in ~e~me, Turkey, August 27-September 7, 1989, the present workshop provided background and current concepts necessary fur the understanding of the microsomal xenobiotic-metabolizing enzymes responsible for the detoxification and activation of endogenous compounds that fmd their way into the body. While the first workshop focused on endogenous substrates of the drug metabolizing enzymes and external toxicants such as benzene and estrogenic pesticides, the second workshop extended this theme to xenobiotic-metabolizing enzymes in aquatic species, as well as to coverage of genotoxicity and chemical carcinogenicity. Progress in the study of xenobiotic metabolizing enzymes in the four years since the last NATO Institute on the topic has been rapid. As a result the lecturers spent time updating the participants on the latest developments and concepts. The rapid expansion of molecular biology into the fields of study of the xenobiotic metabolizing enzymes has given insight into the regulation of these enzymes. The development of heterologous expression systems has provided a basis whereby functions of the enzyme systems can be probed and its impact studied in the living cell. The growing recognition of the serious consequences of environmental pollution has spawned a number of studies on the impact of environmental contaminants on aquatic species, as well as the role of xenobiotic enzymes in chemical carcinogenesis. This book comprises the proceedings of the meeting. The chapters express the material covered by the lecturers, and contain sufficient background information for the beginning student. At the same timet. the material presented is upto-date, and we believe it will provide the latest information and citation to be of benefit to person working in these areas. E. Anne J. B. Sehenkman E. Hodgson

6 Contents Introduction to Cytochrome P450 J. B. Schenkman and I. Jansson 1 General Aspects of NADPH Cytochrome P450 Reductase and Cytochrome b E. Arlnc;: Interaction Between Cytochrome P450 and Reductase J. B. Schenkman and A. I. Voznesensky 47 Molecular Biology of Cytochrome P450: Evolution, structure and Regulation Y. Fujii-Kuriyama and O. Gotoh The Role of Nuclear Receptors in the Regulation of P450s and Other Genes by Peroxisome Proliferators E. F. Johnson, C. N. A. Palmer, M.-H. Hsu and K. J. Griffin Mapping Determinants of the Substrate Specificities of P450s by Site-Directed Mutagenesis T. H. Richardson, M.-H. Hsu and E. F. Johnson Diversity and Regulation of Cytochromes P450 in Aquatic Species J. J. Stegeman Cytochrome P450 Expression in Rainbow Trout: An Overview D. R. Buhler Molecular Aspects of Cytochrome P450 2E1 and Its Roles in Chemical Toxicity C. S. Yang and J.-Y. Hong Problems Associated with Assessment of the Contribution of Individual Forms of Cytochrome P450 to the Metabolism of Xenobiotics R. M. Philpot and L. Overby Emergence of the Flavin-Containing Monooxygenase Gene Family: Molecular Biology, Structure, and Function... " R. M. Philpot, E. A.-A.-Adjei, K. Nikbakht, V. Burnett and M. P. Lawton

7 VIII Flavin-Containing Monooxygenases: Substrate Specificity and Complex Metabolic Pathways E. Hodgson, B. L. Blake, P. E. Levi, R. B. Mailman, M. P. Lawton, R. M. Philpot and M. B. Genter Developmental Regulation of Biotransformation of Drugs and Other Xenobiotics W. Klinger Modulation of Xenobiotic Metabolism and Toxicity by Dietary Chemical C. S. Yang and T. J. Smith Mechanisms of Mutagenicity and Tumour Formation D. Anderson Genotoxici ty Assays D. Anderson Use of Mechanistic Information for Adequate Metabolic Design of Genotoxicity Studies and Toxicological Interactions of Drugs and Environmental Chemicals F. Oesch, F. Fahndrich, H. R. Glatt, B. Oesch Bartlomowicz, K.-L. Platt and D. Utesch Significance of Post translational Modification of Drug Metabolizing Enzymes by Phosphorylation for the Control of Carcinogenic Metabolites F. Oesch, H. J. Arens, F. Fahndrich, T. Friedberg, B. Richter, H. Yamazaki and B. Oesch-Bartlomowicz The Construction of Cell Cultures Genetically Engineered for Metabolic Competence towards Xenobiotics J. Doehmer In Vitro Systems as Analytical Tools for Understanding and Predicting Drug Metabolism In Vivo... '455 J. Doehrner The Role of Oxidative Enzymes in the Metabolism and Toxicity of Pesticides E. Hodgson, R. L. Rose, N. H. Adams, N. J. Demaer, M. B. Genter, K. Venkatesh and P. E. Levi

8 IX Metabolism of Xenobiotic Proestrogens and Estrogens by Cytochrome P D. Kupfer Metabolism of Antiestrogenic Anti-Cancer Agents by Cytochrome P450 and Flavin-Containing Monooxygenases. Mechanism of Action Involving Metabolites D. Kupfer Therapeutic Agents and Cytochrome P A. Y. H. Lu Drug Metabolism, Lipid Peroxidation and Glutathione W. Klinger Health Environment of Altai Territory and Monooxygenase and Conjugating Activities in Placentae of Newborn S. Kotelevtsev, V. V. Obrazsov, C. N. Novicov and L. I. Stepanova Monooxygenase Measurements as Indicators of Pollution in the Field R. F. Addison Biochemical and Genotoxicological Monitoring of Ecosystems with Special Reference to Lake Baikal and Northern Black Sea S. V. Kotolevtsev and L. I. Stepanova Relating Biochemical Responses to "Higher Order" Effects R. F. Addison List of Invited Contributors 605 Index 607