Proceedings in Life Sciences Drugs Affecting Lipid Metabolism Edited by R. Paoletti, D. Kritchevsky and W L. Holmes With 132 Figures Springer- Verlag Berlin Heidelberg New York London Paris Tokyo Professor Dr. RODOLFO PAOLETTI Dean School of Pharmacy University of Milan Via Balzaretti 9 20133 Milan, Italy Professor Dr. DAVID KRITCHEVSKY Associate Director The Wistar Institute 3601 Spruce Street Philadelphia, PA 19104, USA Dr. WILLIAM L. HOLMES 238 Chatham Way West Chester, PA 19380, USA ISBN-13: 978-3-642-71704-8 e-ISBN-13: 978-3-642-71702-4 DOl: 1O.l007/978-3-642-71702-4 Library of Congress Cataloging in Publication Data. Drugs affecting lipid metabolism/ edited by R. Paoletti. D. Kritchevsky, and W.L. Holmes. p, cm. - (Proceedings in life sciences) Includes index. Hyperlipidemia-Chemotherapy. 2. Antilipemic agents-Testing. 3. Blood lipoproteins-Metabolism. 4. Blood cholesterol-Metabolism. I. Paoletti, Rodolfo. II. Kritchevsky, David, 1920-. III. Holmes, Williams L., 1918-. IV. Series. [DNLM: 1. Antilipemic Agents. 2. Arteriosclerosis. 3. Lipids-metabolism. 4. Lipoproteins-metabolism. 5. Metabolism-drug effects. QU 85 0794] RC632.H87D78 987 616.3'997061-dc 19 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1987 Softcover reprint of the hardcover 15t edition 1987 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. 2131/3130-543210 Preface The recent symposium and the appearance of this new book on Drugs Affecting Lipid Metabolism take place at a very unusual time for the development of this area. After the publication and wide acceptance of the results of the cholestyramine study by the Lipid Clinics in the USA, showing for the first time a direct association between drug induced reduction of plasma levels of total and LDL cholesterol and coronary heart disease in a high risk population, an unparalleled interest in drugs and other procedures able to control plasma cholesterol levels has been activated. Two other significant events occurred during 1986 and 1987: the availability of compact instruments for the immediate determination of total cholesterol in plasma or total blood and the developments of new agents such as the inhibitors of HMG-CoA (hydroxymethyl glutaryl CoA) reductase and ACAT inhibitors, with potentially great effect on plasma lipid levels after oral administration. These new advances, together with the combined efforts of cell biologists and lipoprotein chemists, have set the pace for an exciting period of research and clinical applications of diets and drugs af fecting lipids. This volume, which includes the work of many of the leading world laboratories, represents an authoritative and up-to-date ap praisal of the status of the art and a stimulus to future research at laboratory and clinical level in an area of opportunity for clinical and preventive medicine. Milan, October 1987 Rodolfo Paoletti Acknowledgements We thank the contributors for their appreciable efforts in writing the papers for the Drugs Affecting Lipid Metabolism Meeting (Florence, Italy, October 22-25, 1986) upon which the chapters in this volume are based. We are particularly indebted to the Giovanni Lorenzini Foundation for its help and generous support, which made the meeting possible. We are also grateful to the scientific secretaries, Drs. A.L. Catapano and C.R. Sirtori, and to the International Advisory Board for their valuable contributions. The Editors Contents Relationship of Cholesterol to DNA Synthesis in Normal and Cancerous Cells M.D. Siperstein, H. DoVale, and J.R. Silber (With 3 Figures) .... Turnover of HMG-CoA Reductase is Influenced by Phosphorylation R.A. Parker, S.J. Miller, and D.M. Gibson (With 2 Figures) . . . .. 9 Regulation of ACAT K.A. Mitropoulos (With 2 Figures) . . . . . . . . . . . . . . . . . . . .. 14 Dietary and Pharmacological Control of Cholesterol, 7 a-Hydroxylase E. Bosisio (With 3 Figures) . . . . . . . . . . . . . . . . . . . . . . . . .. 21 Recent Advances in Metabolic Pathways of Bile Acid Synthesis N.B. Javitt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 29 Bile Acid Sequestrants: Do They Have a Future? S.M. Grundy .................................... 34 Transport of Cholesterol and Cholesterol Esters by HDL D. Steinberg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 42 Role of HDL in the Metabolism of the Plasma Lipoproteins S. Eisenberg (With 1 Figure) . . . . . . . . . . . . . . . . . . . . . . . .. 48 The Structure of ApoB-IOO: Structure-Function Studies A.M. Gotto, W.A. Bradley, L. Chan, S.H. Gianturco, H.J. Pownall, J.T. Sparrow, and CY. Yang (With 2 Figures) 52 A Genetic Marker in the Apolipoprotein AI/Cm Gene Complex Associated with Hypercholesterolaemia C.C. Shoulders, M.J. Ball, J.1. Mann, and F.E. Baralle ......... 56 VIII Contents Cellular and Molecular Biology of Apolipoproteins: Receptor-Mediated Regulation of Cholesterol Metabolism R.W. Mahley (With 1 Figure) ......................... 59 APOA-I and APOA-II Metabolism and Coronary Artery Disease G. Ghiselli, J. Heibig, F. Turturro, A.M. Gotto, Jr., and E. Wittels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63 Hypocholesterolemic Drugs and Lipoprotein Metabolism D. Steinberg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 69 Hypotriglyceridemic Drugs and Lipoprotein Catabolism S. Eisenberg (With 1 Figure) . . . . . . . . . . . . . . . . . . . . . . . .. 79 Lipolysis and Lipoprotein Metabolism P. Nilsson-Ehle (With 2 Figures). . . . . . . . . . . . . . . . . . . . . .. 83 Regulation of Lipoprotein Lipase Activity: Its Role in Lipid-Lowering Therapies Th. Olivecrona, S.R. Price, P.H. Pekala, R.O. Scow, S.S. Chernick, H. Semb, S. Vilard, and G. Bengtsson-Olivecrona (With 3 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 88 Lipolysis and Antilipolytic Drugs at Different Ages R.M. Gaion and P. Dorigo ........................... 94 Fatty Acid -Binding Proteins of Various Tissues J.H. Veerkamp and R.J.A. Paulussen (With 3 Figures) ........ 98 Interaction of Lipid-Lowering Drugs with Fatty Acid-Binding Proteins N.M. Bass and R.K. Ockner (With 1 Figure) ............... 105 Animal Models for Hyperlipidemia-Induced Atherosclerosis R.w. Wissler and D. Vesselinovitch (With 2 Figures) .......... III Animal Species as Models of Spontaneous and Induced Hyperlipidemias: A Critical Appraisal M .J . Chapman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Rabbit Models Hypo-or Hyperresponsive to Changes in Diet A.C. Beynen, A.G. Lemmens, J.F.C. Glatz, M.B. Katan, and L.F M. Van Zutphen ........................... 122 Contents IX Plasma Lipoproteins and Cholesterol Metabolism in a Strain of Hyperlipemic Rats S. Fantappie, E. Bosisio, M. Crestani, G. Galli, and A.L. Catapano (With 2 Figures) .................... 126 Spontaneous Hypertriglyceridemia in a Non-Obese Rat Model: The IV A-SIV Rat M.R. Lovati, L. Allievi, C. Manzoni, C. Galli, and C.R. Sirtori (With 1 Figure). . . . . . . . . . . . . ..................... 131 Considerations for Controlled Clinical Testing of Safety and Efficacy of New Hypolipidemic Drugs C.A. Dujovne and P. Krehbiel (With 7 Figures) ............. 136 Desirable Lipoprotein Parameters in Early Drug Trials C.R. Sirtori and A. Bondioli (With 4 Figures) .............. 142 Metabolic Studies with Lovastatin in Patients with Primary Hypercholesteremia D.B. Hunninghake, D.M. Hibbard, W.C. Duane, M.L. Freeman, W.F. Prigge, K.J. Graham, and R.L. Gebhard (With 2 Figures) ... 150 Reduction of Plasma Lipids and Lipoproteins by Dietary Fish Oils in Patients with Hypertriglyceridemia B.E. Phillipson, W.E. Connor, W.S. Harris, and D.R. Illingworth .. 155 Effects of Monounsaturated Fatty Acids Versus Complex Carbohydrates on Serum Lipoprotein Subfractions and Apolipoproteins in Healthy Men and Women R.P. Mensink and M.B. Katan ................. _ ..•... 158 Changes of Eicosanoid Formation in Relation to Dietary Lipids and in Hyperlipaemia C. Galli, C. Mosconi, L. Medini, and E. Tremoli ............. 162 Effects of Omega-3 Polyunsaturated Fatty Acids on Human Leukocyte Function and Biochemistry R.I. Sperling and K.F. Austen ........................ 167 Dietary and Biochemical Studies with Textured Soy Proteins C .R. Sirtori, A. Canavesi, C. Manzoni, and M.R. Lovati (With 3 Figures) ................................. 174 Detection of Reactive Free Radicals in Livers of Ethanol-Fed Rats: Potentiating Effect of High Fat Diets P.B. McCay and L.A. Reinke (With 6 Figures) .............. 181 x Contents The Role of the Antioxidant Tocopherol in Lipid and Lipoprotein Metabolism H.J. Kayden and M.G. Traber ........................ 193 Newer Aspects of Fats and Lipid Metabolism D. Kritchevsky .................................. 197 Can We Retard Atherogenesis by Modifying High-Density Lipoprotein Metabolism? N.E. Miller (With 1 Figure) .......................... 200 Effects of Lipid-Lowering Drugs on High Density Lipoprotein Structure and Metabolism J. Shepherd and C.J. Packard (With 1 Figure) .............. 205 Enzyme-Inducers and High-Density Lipoproteins P.V. Luoma (With 2 Figures) ......................... 210 Gonadal Steroids and Hormone Antagonists D. Crook, I.F. Godsland, J.C. Montgomery, and V. Wynn ...... 215 The Effects of Adrenoceptor and Adrenergic Blocking Drugs on Plasma Lipoproteins A. Lehtonen .................................... 219 The Influence of Terpenes and Analogues on Parameters of Atherosclerosis DA. White, G.D. Bell, F. Cacciaguerra, and B. Middleton (With 1 Figure) .................................. 223 Initial Stages of Reverse Transport of Cholesterol D. Reichl (With 1 Figure) ........................... 227 Lipolytic Enzymes and HDL: Influence of Drugs and Hormones M.-R. Taskinen and E.A. Nikkilii (With 2 Figures) ........... 231 Human Apolipoprotein A-I and A·II Metabolism H.B. Brewer, Jr., R.E. Gregg, S.W. Law, J.M. Hoeg, and L.A. Zech (With 3 Figures) ....................... 236 Roles of LCAT and Lipid Transfer Protein in HDL Metabolism P.J. Barter and G.J. Hopkins ......................... 244 The ProfIle of an HMG-CoA Reductase Inhibitor, CS-514 (SQ 31,000) Y. Goto (With 2 Figures) ........................... 247 Contents XI Induction of Hepatic Low-Density Lipoprotein Receptors in Heterozygous WHHL Rabbits Treated with CS-514 Alone or CS-514 in Combination with Cholestyramine T. Kita, N. Kume, Y. Tsujita, T.lto, Y. Watanabe, and C. Kawai (With 2 Figures) ................................. 251 The Clinical Pharmacology of SQ 31,000 (CS 514) in Healthy Subjects H.Y. Pan, D.A. Willard, P.T. Funke, and D.N. McKinstry (With 3 Figures) ................................. 255 Long-Term Effects of CS-514 on Serum Lipoprotein Lipid and Apolipoprotein Levels in Patients with Familial Hypercholesterolemia H. Mabuchi; N. Kamon, H. Fujita, I. Michishita, M. Takeda, K. Kajinami, H.ltoh, T. Wakasugi, and R. Takeda (With 6 Figures) ................................. 260 Intensive Drug Treatment for Familial Hypercholesterolemia A. Yamamoto, S. Yokoyama, and T. Yamamura (With 3 Figures). 269 Effect ofCS-514 on Hypercholesterolemic Patients N. Nakaya and Y. Goto (With 5 Figures) ................. 274 Hyperlipoproteinemia and Therapy: Results of a Multicenter Trial with Bezafibrate, a New Lipid-Lowering Drug D. Sommariva and A. Branchi ........................ 278 Lipoprotein Changes Induced by Bezafibrate - 200 mgt.i.d. - and by Bezafibrate in a Slow-Release Preparation - 400 mg Once a Day - in Patients with Primary Hyperlipoproteinaemia S. Bertolini, S. Valice, N. Elicio, A. Daga, S. Cuzzolaro, G. Montagna, G. Pistocchi, and R. Balestreri. .............. 283 Modifications of Apoprotein, Lipoprotein Parameters and HDLz and HDL3 Sub fractions During Treatment with Bezafibrate Retard A. Ventura, E. Mannarino, G. Ciuffetti, D. Siepi, and G. Lupattelli ................................. 291 Effect of Bezafibrate Retard on Plasma Lipoproteins in Hypertriglyceridemic Patients With and Without Diabetes Mellitus G. Riccardi, G. Saldalamacchia, S. Genovese, L. Patti, G. Marotta, A. Postiglione, A. Rivellese, B. Capaldo, and M. Mancini ....... 295 Long-Term Experience of a Single Daily Dose of Bezafibrate Retard 400 in Hyperlipoproteinaemia of Types IIa, lIb and IV W. Schwartzkopff ................................ 301