Peroxisomes: Biology and Importance in Toxicology and Medicine Peroxisomes: Biology and Importance in Toxicology and Medicine Edited by Gordon Gibson and Brian Lake Taylor & Francis London Washington, DC 1993 UK Taylor & Francis Ltd, 4 John St., London WC1N 2ET USA Taylor & Francis Inc., 1900 Frost Rd., Suite 101, Bristol, PA 19007 © Taylor & Francis Ltd. 1993 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner. British Library Cataloguing in Publication Data are available on request from the British Library ISBN 07484-0053-2 Library of Congress Cataloging-in-Publication Data are available on request Cover design by Amanda Barragry Typeset in 10/12 Times by RGM/Witwell Assoc., Southport Printed in Great Britain by Burgess Science Press, Basingstoke on paper which has a specified pH value on final paper manufacture of not less than 7.5 and is therefore 'acid free'. Contents Preface ix Contributors xiii 1. Peroxisome biogenesis G. M. Small 1 2. Metabolic role of mammalian peroxisomes G. P. Mannaerts and P. P. Van Veldhoven 19 3. Peroxisomal disorders R. J. A. Wanders, P. G. Barth, R. B. H. Schutgens and J. M. Tager 63 4. The molecular mechanism of peroxisome proliferator action S. Green, I. Issemann and J. D. Tugwood 99 5. Peroxisome proliferators as cytochrome P450 inducers G. G. Gibson, E. Chinje, O. Sabzevari, P. Kentish and D. F. V. Lewis 119 6. Peroxisome proliferation — lipid metabolism and receptors D. R. Bell and C. R. Elcombe 137 7. Molecular mechanisms involved in induction of peroxisomal â-oxidation enzymes by hypolipidaemic agents T. Osumi, J.-K. Wen, S. Taketani and T. Hashimoto 149 8. Molecular basis of gene regulation by peroxisome proliferators N. Latruffe, M. Bugaut, P. Bournot, M. Bentejac, L. C. Ramirez and M. Cherkaoui Malki 173 9. Molecular evolution of the urate oxidase encoding gene and its functional significance A. V. Yeldandi and V. Yeldandi 205 í vi Contents 10. Possible role of CoASH esters on xenobiotic-induced peroxisomal proliferation and non-genotoxic carcinogenesis M. Bronfman 217 11. Modulation of peroxisomal biogenesis and lipid metabolising enzymes by dietary factors T. Flatmark and Å. N. Christiansen 247 12. Proliferation of peroxisomes and mitochondria and modulation of lipid metabolizing enzymes by hypolipidaemic, non-â-oxidizable fatty acids (3-thia fatty acids) R. K. Berge, Ç. Kryvi, Í. Aarsaether, A. Aarsland and J. Skorve 277 13. Cultured hepatocytes: a useful in vitro system to investigate effects induced by peroxisome proliferators and their species specificity F. Bieri 299 14. Structure-activity relationships for chemically induced peroxisome proliferation in mammalian liver B. G. Lake and D. F. V. Lewis 313 15. Tetrazole substituted acetophenone peroxisome proliferators: structure-activity relationships and effects on hepatic lipid metabolism P. J. Eacho, P. S. Foxworthy and D. K. Herron 343 16. Structural requirements for peroxisome proliferation by phenoxyacetic and fatty acid analogues in primary cultures of rat hepatocytes D. R. Feller and U. Intrasuksri 373 17. Ultrastructural and biochemical aspects of peroxisome proliferation and biogenesis in different mammalian species H. D. Fahimi, E. Baumgart, Ê. Beier, J. Pill, F. Hartig and A. Völkl 395 18. Toxicological studies in primates with three fibrates M. J. Tucker and T. C. Orton 425 19. Structure-, enantiomer- and species-specific effects of fibrate analogues on peroxisome proliferation and increased activity of mitochondrial á-glycerophosphate dehydrogenase B. R. Holloway and J. M. Thorp 449 Contents vu 20. Metabolism of di-(2-ethylhexyl)phthalate (DEHP) and di-(2-ethylhexyl) adipate (DEHA) and their relationship to peroxisome proliferation in different species J. C. Lhuguenot and M. C. Cornu 465 21. Extrahepatic peroxisome proliferation and the extrahepatic effects of peroxisome proliferators R. H. Hinton and S. C. Price 487 22. Biological aspects of peroxisome proliferator-induced liver tumours in the rat M .S. Rao and J. K. Reddy 513 23. Genotoxicity studies of peroxisome proliferators J. D. Budroe and G. M. Williams 525 24. Production of 8-hydroxydeoxyguanosine in rodent liver by the administration of peroxisome proliferators A. Takagi, K. Sai, T. Umemura, R. Hasegawa and Y. Kurokawa 569 25. Role of oxidative stress and enhanced cell replication in the hepatocarcinogenicity of peroxisome proliferators B. G. Lake 595 26. Hyperplastic responses to peroxisome proliferators J. A. Styles 619 27. Hepatic changes associated with peroxisome proliferation P. Grasso 639 28. Peroxisome proliferators as initiators and promoters of rodent hepatocarcinogensis J. A. Popp and R. C. Cattley 653 29. Are peroxisome proliferators tumour promoters in rat liver? B. Grasl-Kraupp, W. Huber and R. Schulte-Hermann 667 30. Risk assessment of chemicals inducing peroxisome proliferation W. T. Stott and N. C. Hawkins 695 Preface Peroxisomes (or 'microbodies') are single membrane-limited cytoplasmic organelles present in cells of animals, plants, fungi and protozoa. Studies by De Duve and coworkers demonstrated that rat liver peroxisomes contain both hydrogen peroxide generating oxidase enzymes and catalase. Later studies by Lazarow and De Duve demonstrated that liver peroxisomes, like mitochon- dria, contain a complete fatty acid â-oxidation cycle, whereas Hess and coworkers first reported that clofibrate, a hypolipidaemic drug, could produce hepatic peroxisome proliferation in the rat. Since these pioneering studies, much effort has been devoted to elucidating the biochemical properties of these organelles and their response to chemicals and other stimuli. The various chapters contained in this volume cover all aspects of the structure, function, regulation and response to chemicals of mammalian peroxisomes. The biogenesis of peroxisomes in various species is considered by Small, whereas the metabolic role of peroxisomes is described by Mannaerts and Van Veldhoven. Peroxisome disorders in man are reviewed by Wanders and coworkers. Several chapters consider the mechanism of initiation of peroxisome proliferation in hepatocytes together with aspects of the molecular biology of peroxisomes and peroxisomal enzymes. Green and coworkers describe the molecular mechanism of peroxisome proliferator action which appears to involve one or more peroxisome proliferator-activated receptors. The mecha- nism of initiation of peroxisome proliferation, together with the interaction with lipid metabolism and receptors is covered by Bell and Elcombe. Rodent liver peroxisome proliferators are known to induce cytochrome P450 isoenzymes in the CYP4A subfamily and the relationship of this phenomenon to the mechanism of peroxisome proliferation is discussed by Gibson and coworkers. The molecular basis of gene regulation by peroxisome proliferators is also reviewed by Latruffe and coworkers, whereas Osumi and coworkers describe in-depth studies on the regulatory sequence of the acyl-CoA oxidase gene. The molecular evolution and functional significance of the urate oxidase gene is reviewed by Yeldandi and Yeldandi. Many peroxisome proliferators or their subsequent metabolites contain a free carboxyl group and hence may form coenzyme A esters. The synthesis of such esters and their possible role in peroxisome proliferation and the hepatic effects of peroxisome proliferation is IX