Springer KK K. Okita (Ed.)

HCV / Oxidative Stress and Liver Disease

With 45 Figures

Springer KIWAMU OKITA, M.D., Ph.D. Professor and Chairman Department of Gastroenterology and Hepatology University School of Medicine 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan

ISBN 978-4-431-67007-0 ISBN 978-4-431-67005-6 (eBook) DOI 10.1007/978-4-431-67005-6

Library of Congress Cataloging-in-Publication data applied for.

Printed on acid-free paper

© Springer Japan 2003 Originally published by Springer-Verlag Berlin Heidelberg New York in 2003 Softcover reprint ofthe hardcover Ist edition 2003 This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of iIIustrations, recitation, broad• casting, reproduction on microfilms or in other ways, and storage in data banks. 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. Product liability: The publisher can give no guarantee for information about drug dosage and appli• cation thereof contained in this book. In every individual case the respective user must check its accu• racy by consulting other pharmaceuticalliterature. Typesetting: SNP Best-set Typesetter Ltd., Hong Kong

SPIN: 10853586 Preface

Since the discovery of superoxide dismutase (SOD) by McCord and Friedovich in 1968, there has been rapid growth in our knowledge of oxidative stress and disease. Now the possible involvement of SOD both in normal basic biology and in digestive disease is well known. According to a report by the Japanese Ministry of Health, Welfare and Labor, the mortality rate of hepatocellular carcinoma (HCC), mainly of hepatitis C virus (HCV)• infected patients, is more than 30 per 100,000 population. The major clinical mani• festations of chronic infection are portal and lobular inflammation with associated hepatocyte necrosis, progressive fibrosis eventually leading to cirrhosis, and develop• ment of hepatocellular carcinoma. In addition, chronic HCV infection sensitizes the liver to injury by alcohol, and these two forms of liver injury appear to be synergistic. Some chapters in this volume of proceedings discuss the direct cellular effects of HCV proteins on hepatocytes and review the evidence that oxidative stress, caused primarily by the HeV core protein, plays a key role in disease pathogenesis. Also presented here are new aspects of oxidative stress in liver disease, e.g., carbon monoxide/iron. This collection provides an important resource for physicians and hepatologists. We thank the Otsuka Pharmaceutical Co., Ltd., for their continuing support.

ORGANIZING COMMITTEE OF THE YAMAGUCHI SYMPOSIUM ON LIVER DISEASE Kiwamu Okita, M.D., Yamaguchi University, Ube Kenichi Kobayashi, M.D., University, Kanazawa Masamichi Kojiro, M.D., , Kurume Masao Ornata, M.D., The University of Tokyo, Tokyo Norio Hayashi, M.D., University, Osaka

SECRETARY GENERAL Isao Sakaida, M.D., Yamaguchi University, Ube

v Table of Contents

Preface...... V List of Participants ...... IX

Alcohol-HCV Interactions in Transgenic Mice Expressing Viral Proteins in the Liver M. OKUDA, L.A. SHOWALTER, K. OTANI, M.R. BEARD, S.Y. XIAO, S.M. LEMON, and S.A. WEINMAN ......

Role of Core Protein-Induced Oxidative Stress in the Pathogenesis of Hepatitis C S.A. WEINMAN, M. OKUDA, K. LI, L.A. SHOWALTER, K. OTANI, S.M. LEMON, and M.R. BEARD ...... 8 Hepatitis C Virus Core-Mediated Alteration of Gene Expression and Signal Transduction in the Host Cell K. OHKAWA, A. HOSUI, Y. SASAKI, and N. HAYASHI...... 19

Signals Induced by HCV Proteins M. OTSUKA, N. KATO, H. TANIGUCHI, H. YOSHIDA, Y. SHIRATORI, and M. OMATA ...... 32 Role of Hepatitis C Virus in Hepatocarcinogenesis: Oxidative Stress in the Absence of Inflammation K. KOIKE and K. MORIYA ...... 48 Reduced Chemical Hepatocarcinogenesis in Interferon-y Receptor Knockout Mice M. MATSUDA, Y. NAKAMOTO, S. KANEKO, and K. KOBAYASHI ...... 58

Fewer Somatic Mutations of Mitochondrial DNA in Noncancerous Liver Tissue Patients with Hepatocellular Carcinoma Respond to Interferon Therapy S. NISHIGUCHI, M. NISHIKAWA, M. INOUE, S. SHIOMI, A. TAMORI, D. HABU, T. TAKEDA, H. KINOSHITA, and S. KUBO ...... 67

Hepatic Iron Staining in Chronic Hepatitis C Patients with Low HCV RNA Levels as a Predictive Marker for Interferon Therapy T. IDE, F. AKIYOSHI, M. SATA, Y. UCHIMURA, H. SUZUKI, and K. TANIKAWA . . . 76

VII VIII Table of Contents

Hepatic Iron Accumulation and Incidence of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C N. IZUMI, Y. ASAHINA, O. NOGUCHI, M. UCHIHARA, S. KAWAMURA, K. TSUCHIYA, K. HAMANO, J. ITAKURA, S. MIYAKE, and T. ...... 83 Carbon Monoxide as a Gaseous Regulator of Liver Microcirculation M. SUEMATSU and S. KASHIWAGI ...... 91 Tamoxifen -Induced Nonalcoholic Steatohepatitis T. SAIBARA, Y. OGAWA, N. XU, Y. NEMOTO, M. ONO, A. WAKATSUKI, K. TODA, H. ENZAN, and S. ONISHI ...... 96

Subject Index...... 105 List of Participants

Asahina, Yasuhiro Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

Hayashi, Norio Department of Internal Medicine and Therapeutics Osaka University Graduate School of Medicine Osaka, Japan

Hino, Keisuke Department of Gastroenterology and Hepatology Yamaguchi University School of Medicine, Ube, Japan Ichida, Takafumi Third Department of Internal Medicine, School of Medicine, University, Niigata, Japan Ide, Tatsuya Second Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Izumi, Namiki Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

Kayano, Kouzo Department of Gastroenterology and Hepatology Yamaguchi University School of Medicine, Ube, Japan Kobayashi, Kenichi Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan Kodama, Takahiro Department of Internal Medicine/Gastroenterology Yamaguchi Central Hospital, Yamaguchi, Japan Koike, Kazuhiko Department of Infectious Diseases, Internal Medicine Graduate School of Medicine, The University of Tokyo Tokyo, Japan Kojiro, Masamichi First Department of Pathology, Kurume University School of Medicine, Kurume, Japan

Kumashiro, Ryukichi Second Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

Matsuda, Mitsuru Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

IX X List of Participants

Moriya, Kyoji Department of Infectious Diseases, Internal Medicine Graduate School of Medicine, The University of Tokyo Tokyo, Japan Nakanishi, Toshio First Department of Internal Medicine, University School of Medicine, Hiroshima, Japan Nishiguchi, Shuhei Department of Hepatology, Osaka City University Medical School, Osaka, Japan Ohkawa, Kazuyoshi Department of Internal Medicine and Therapeutics Osaka University Graduate School of Medicine Osaka, Japan Okita, Kiwamu Department of Gastroenterology and Hepatology Yamaguchi University School of Medicine, Ube, Japan Okuda, Michiari Department of Gastroenterology and Hepatology Yamaguchi University School of Medicine, Ube, Japan Ornata, Masao Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Onishi, Saburo First Department of Internal Medicine, Kochi Medical School, Kochi, Japan Otsuka, Motoyuki Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Saibara, Toshiji First Department of Internal Medicine, Kochi Medical School, Kochi, Japan Sakaida, Isao Department of Gastroenterology and Hepatology Yamaguchi University School of Medicine, Ube, Japan Suematsu, Makoto Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan Tanikawa, Kyuichi International Institute for Liver Research, , Japan Terai, Syuji Department of Molecular Science and Applied Medicine Yamaguchi University School of Medicine, Ube, Japan Weinman, Steven A. Department of Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch Texas, USA