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BIOLOGICAL REACTIVE INTERMEDIATES IV Molecular and Cellular Effects and Their Impact on Human Health

Edited by

Charlotte M. Witmer and Robert R. Snyder Rutgers University Piscataway, New Jersey

David J. Jollow Medical University of South Carolina Charleston, South Carolina

George F. Kalf and James J. Kocsis Thomas Jefferson University Philadelphia, Pennsylvania

and

I. Glenn Sipes University of Arizona Tucson, Arizona

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

International Symposium on Biological Reactive Intermediates (4th: 1990: Tucson, Ariz.)

Biological reactive intermediates IV: molecular and cellular effects and their impact on human health I edited by Charlotte M. Witmer ... let al.).

p. cm. - (Advances in experimental medicine and biology: v. 283) "Proceedings of the Fourth International Symposium on Biological Reactive Inter-

mediates, held January 14-17, 1990, in Tucson, Arizona" - T.p. verso. Includes bibliographical references and index. ISBN 978-1-4684-5879-4 ISBN 978-1-4684-5877-0 (eBook) DOI 10.1007/978-1-4684-5877-0 I. Biotransformation (Metabolism) - Congresses. 2. Biochemical toxicology - Con­

gresses. I. Witmer, Charlotte M. II. Title. III. Title: Biological reactive intermediates 4. IV. Series.

[DNLM: I. Biotransformation-congresses. 2. Toxicology-congresses. WI AD559 v.283 I QV 600 I63b 1990) RA1220.I58 1990 615.9-dc20 DNLM/DLC for Library of Congress

Proceedings of the Fourth International Symposium on Biological Reactive Intermediates, held January 14-17, 1990, in Tucson, Arizona

© 1991 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1991

A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013

All rights reserved

90-14326 CIP

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

PREFACE

The finding that chemicals can be metabolically activated to yield reactive chemical species capable of covalently binding to cellular macromolecules and the concept that these reactions could initiate toxicological and carcinogenic events stimulated a meeting by a small group of toxicologists at the University of Turku, in Finland, in 1975 (Jollow et al., 1977). The growing interest in this field of research led to subsequent symposia at the University of Surrey, in England in 1980 (Snyder et al., 1982), and the University of Maryland in the U.S.A. in 1985 (Kocsis et al., 1986). The Fourth International Symposium on Biological Reactive Intermediates was hosted by the Center for Toxicology at the University of Arizona and convened in Tucson, Arizona, January 14-17, 1990. Over 300 people attended. There were 60 platform presentations by invited speakers, and 96 volunteer communications in the form of posters were offered. These meetings have grown from a small group of scientists working in closely related areas to a major international series of symposia which convene every five years to review, and place in context, the latest advances in our understanding of the formation, fate and consequences of biological reactive intermediates.

The Organizing Committee: Allan H. Conney, Robert Snyder (Co-chairman), and Charlotte M. Witmer (Rutgers University, Piscataway, NJ), David J. Jollow Co­chairman) (Medical University, South Carolina, Charleston, SC), 1. Glenn Sipes (Co­chairman) (University of Arizona, Tucson, AZ), James J. Kocsis and George F. Kalf (Thomas Jefferson University, Philadelphia, PA), and Donald J. Reed (Oregon State University), developed the program on the basis of a series of communications with the members of the International Program Committee: M.W. Anders (University of Tubingen), A. Jay Gandolfi (University of Arizona), G. Gordon Gibson (University of Surrey), James R. Gillette (National Institutes of Health), Doyle G. Graham (Duke University), Ronald W. Estabrook (University of Texas), Helmut Greim (GSF, Munich), James Halpert (University of Arizona), Jack Hinson (National Center for Toxicological Research), Daniel C. Liebler (University of Arizona), Lance Pohl (National Institutes of Health), John B. Schenk man (University of Connecticut). The result was a program which encompassed a broad range of areas related to the field of biological reactive intermediates, the role of reactive oxygen, carcinogenesis, the application of new techniques in molecular biology to study biological reactive intermediates, the use of information relating to biological reactive intermediates as biomarkers of exposure, and the study of biological reactive intermediates in humans.

These meetings are not sponsored by a major society. It falls upon the organizing committee to secure funding for the symposium. The committee expresses their gratitude to the following organizations for contributing to the support of the symposium. Supporters among government agencies included the National Institute for Environmental Health Sciences, the U.S. Environmental Protection Agency, the Agency for Toxic SulJstances and Disease Registry, the U.S. Army, and the U.S. Air Force. In addition, industrial support came from Beckman Instruments, the Burroughs WeUcome Company, the Dow Chemical Company, Eli Lilly and Company, Hoffmann­LaRoche, Inc., Glaxo, Inc., ICI Americas, Inc., G.D. Searle and Company, Merck Sharp and Dohme Research Laboratories, the Proctor and Gamble Company, Smith Kline Beecham, Sterling Winthrop Research Institute, and the Upjohn Company. Support from academic institutions came from the University of Arizona Center for

v

Toxicology, and from the Environmental and Occupational Health Sciences Institute and the Joint Graduate Program in Toxicology of Rutgers University and The University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School.

It is not possible to mount a major international symposium without the dedicated effort of session chairpeople. The session chairs contributed programmatic ideas prior to the meeting and kept the program on track during the meeting. We express our gratitude to Ronald W. Estabrook (University of Texas), Steven D. Aust (Utah State University), Robert P. Hanzlik (Kansas State University), A. Jay Gandolfi (University of Arizona), Allan H. Conney (Rutgers University), G. Tim Bowden (University of Arizona), Dietrich W. Henschler (University of Wurzburg), Hermann Kappus (Free University of Berlin), Donald S. Davies (University of Arizona), Peter Farmer (Medical Research Council), Roger O. McClellan (Chemical Industry Institute of Toxicology).

Professor Elizabeth C. Miller, who played an important role in the previous Biological Reactive Intermediates Symposia, died in the time between the third and fourth in this series of sy mposia.. She, along with her husband and collaborator, Professor James A. Miller, reported the original observation of the covalent binding phenomenon. Together, they helped open up a whole new area of investigation for two generations of scientists. The organizing committee wishes to pay tribute to the memory of Betty Miller for her fundamental scientific contributions and for the enthusiasm with which she participated in these conferences.

Critical to the success of these symposia has been the selection of an appropriate venue and this year we were particularly fortunate in having asked the Center for Toxicology at the University of Arizona, directed by Professor I. Glenn Sipes to act as host. The stimulating scientific spirit, the hospitality, and the excellent facilities located against the background of the great southwestern desert created an ideal locale for these deliberations. We are forever indebted to Professor Sipes and the local organizing committee (Professors Daniel C. Liebler, A. Jay Gandolfi and James R. Halpert) for providing the environment in which our colleagues from around the world could gather, com municate and learn together.

Without doubt, the people who worked hardest to insure the success of the conference were the administrators and secretarial staff including Sena Taylor, Charleen Prytula, Kathy Sousa, Pamela Murray, Bert Sanchez and Judith Stanfield of the University of Arizona and Catherine Raymore and Bernadine Chmielowicz of Rutgers University.

The field of biological reactive intermediates has grown to include toxicologists, bioche mists, oncologists, pathologists, che mists, physicians, epide m iologists, geneticists, molecular biologists and scientists in an increasing circle of related disciplines. The need for interdisciplinary approaches to the solution of basic biomedical problems has of necessity lead to the dissolution of boundaries between the classical disciplines. The benefit to the individual scientist is the opportunity to expand one's horizons and to grow intellectually. The benefit to man is that we can more readily approach solutions to key problems in human health. The meeting in Arizona demonstrated once again that our colleagues from around the world can join together with the common goal of understanding chemically induced human disease. Of equal importance was that once again we demonstrated that this could be accomplished in an atmosphere of collegiality, appreciation of the talents of our fellow scientists, and the comradeship which attracts us to meet together on a regular basis to continue our discussion.

vi

Charlotte M. Witmer Robert Snyder David J. Jollow George F. Kalf James J. Kocsis I. Glenn Sipes

CONTENTS

SESSIONS I - VI

Cytochrome P-450 Oxidations and the Generation of Biologically Reactive Intermediates .•.•..••..•...••...••..••••••.•••. 1 F. Peter Guengerich, Tsutomu Shimada, Arnaud Bondon, and Timothy L. Macdonald

Formation of Reactive Intermediates by Phase II Enzymes: Glutathione-Dependent Bioactivation Reactions •.••••.....•...••.•.•.......•••••.••••..••.• 13 Spyridon Vamvakas, and M. W. Anders

Role of the Well-Known Basic and Recently Discovered Acidic Glutathione S-Transferases in the Control of Genotoxic Metabolites •••..••.•••.••••.•••••••.•••.••.• 25 Franz Oesch, Ingolf Gath, Takashi Igarashi, Hansruedi Glatt, Barbara Oesch-Bartlomowicz, and Helmut Thomas

Bioactivation of Xenobiotics by Flavin-Containing Monooxygenases •..•••..•.•..•••........••.•••••••..••• 41 Daniel M. Ziegler

Formation of Biological Reactive Intermediates By Peroxidases: Halide Mediated Acetaminophen Oxidation and Cytotoxicity .....•..•.•.......•••.•••••••••••.••.•. 51 Peter J. O'Brien, Sumsullah Khan, and Samuel D. Jatoe

Peroxyl Free Radicals: Biological Reactive Intermediates Produced During Lipid Oxidation ...........•••••••.•••..••. 65 Lawrence J. Marnett

Biological Significance of Active Oxygen Species: In Vitro Studies on Singlet Oxygen-Induced DNA Damage and on the Singlet Oxygen Quenching Ability of Carotenoids, Tocopherols and Thiols •..•..••...••...•...•..•••••••.•.. 71 Paolo Di Mascio, Stephan P. Kaiser, Thomas, P.A. Devasagayam, and Helmut Sies

Physiological and Toxicological Roles of Hydroperoxides •••••.••••••••.••..•......•.••.•..•••••• 79 V. Ullrich, M. Schatz, and F. Meisch

Overview: Theoretical Aspects of Isotope Effects on the Pattern of Metabolites Formed by Cytochrome P-450 ..•...............•..•.•..•••.•••.••. 87 James R. Gillette, and Kenneth Korzekwa

vii

S-Thiolation of Protein Sulfhydryls ••••••••••••••••••••••••••••••• 95 James A. Thomas, Eun-Mi Park, Yuh-Cherng Chai, Robert Brooks, Kazuhito Rokutan, and Richard B. Johnston, Jr.

Cytochrome P-450 as a Target of Biological Reactive Intermediates •••••.••.••••••••••••••.••••••.•.••••••• 105 James R. Halpert, and Jeffrey C. Stevens

Hapten Carrier Conjugates Associated with Halothane Hepatitis ••••.••••.•.••••••.••••••••••••••••••••.••• 111 Lance R. Pohl, David Thomassen, Neil R. Pumford, Lynn E. Butler, Hiroko Satoh, Victor J. Ferrans, Andrea Perrone, Brian M. Martin, and Jackie L. Martin

Metabolism of Drugs by Activated Leukocytes: Implications for Drug-Induced Lupus and Other Drug Hypersensitivity Reactions ..••.•••.••••••••••••••••••••• 121 Jack Uetrecht

Formation of Reactive Metabolites and Appearance of Anti-Organelle Antibodies in Man ••••••••.••••••••••••..••• 133 D. Mansuy

Formation of a Protein-Acetaldehyde Adduct in Liver During Chronic Alcohol Exposure ••••••.•.••••••••••••••••• 139 Renee C. Lin, and Lawrence Lumeng

Dose-Response Relationships in Chemical Carcinogenesis: From DNA Adducts to Tumor Incidence •••.••••..••••••••••. 151 Werner K. Lutz

The Single Cell Gel (SCG) Assay: An Electrophoretic Technique for the Detection of DNA Damage in Individual Cells ••.......•...•.•••••••••••••••.•••••• 157 R.R. Tice, P.W. Andrews, O. Hirai, and N.P. Singh

Monitoring Human Exposure to Environmental Carcinogens ••••.••.•.•• 165 Regina M. Santella, Yu Jing Zhang, Tie Lan Young, Byung Mu Lee, and Xiao Qing Lu

Comparing the Frequency and Spectra of Mutations Induced When an SV40-Based Shuttle Vector Containing Covalently Bound Residues of Structurally-Related Carcinogens Replicates in Human Cells •••••••...••....••••••••••••••••••••••• 183 Veronica Maher, Jia-Ling Yang, M. Chia-Miao Mah, Yi-Ching Wang, Janet Boldt, and J. Justin McCormick

Molecular Targets of Chemical Mutagens ••••.••.••••••.••.••.•••. 193 Bradley D. Preston, and Rupa Doshi

Mutagenic Consequences of the Alteration of DNA by Chemicals and Radiation •••••••.•..•...••••..••.••••.••.••...•.• 211 Bernard Strauss, Edith Turkington, Jhy Wang, and Daphna Sagher

Gene Specific Damage and Repair After Treatment of Cells

viii

with UV and Chemotherapeutical Agents ••.•••••.••.••••••.• 225 Vilhelm A. Bohr

Proto-Oncogene Activation in Rodent and Human Tumors .•••••••••••• 235 Marshall W. Anderson, Ming You, and Steven H. Reynolds

SHORT COMMUNICATIONS

Toxicity of 3-Methyleneoxindole, A Proposed Reactive Intermediate in the Metabolism of 3-Methylindole •••••••••••••••••••••••• 245 Martin L. Appleton, Douglas N. Larson, Gary L. Skiles, William K. Nichols, and Garold S. Yost

The Role of Cytochrome P450IIE1 in Bioactivation of Acetaminophen in Diabetic and Acetone-Treated Mice •••••••••••••••••••••• 249 E.H. Jeffery, K. Arndt, and W.M. Haschek

Arylamine-Induced Hemolytic Anemia: Electron Spin Resonance Spectrometry Studies ••••••••••••••••••••••••••••••••••• 253 Timothy P. Bradshaw, D.C. McMillan, R.K. Crouch, and D.J. Jollow

Selective Alterations in the Profiles of Newly Synthesized Proteins by Acetaminophen (APAP) and Its Dimethylated Analogues: Relationship to Oxidative Stress •••••••••••••••••• 257 Mary K. Bruno, Steven D. Cohen, and Edward A. Khairallah

Benzene Metabolism by Two Purified, Reconstituted Rat Hepatic Mixed Function Oxidase Systems •.•••••••••••••••••• 261 Thomas A. Chepiga, Chung S. Yang, and Robert Snyder

Stereochemical Induction of Cytochrome P450IVA1 (P452) and Peroxisome Proliferation in Male Rat •••••••••••••••••••• 267 Edwin C. Chinje, and G. Gordon Gibson

Cyanide Liberation and Oxidative Stress by Organothiocyanates, Organonitriles and Nitroprusside in Isolated Hepatocytes •••.••.•••••••••••••••••••••••••••• 271 Sahar Elguindi, and Peter J. O'Brien

Mixed Function Oxidase Enzyme Responses to In Vivo and In Vitro Chromate Treatment ••••••••••••••••••••••••••••• 275 Ellen C. Faria, and Charlotte M. Witmer

Fatty Acid j3-0xidation-Dependent Bioactivation of 5,6-Dichloro-4-Thia-5-Hexenoate and Analogs in Isolated Rat Hepatocytes ••••.•••••••••••••••••••••••••••••••••••• 281 M. E. Fitzsimmons, and M. W. Anders

Role of the Acetone Inducible P-450IIE1 in the Deethylation of Diethylnitrosamine In Hamster •••••••••••••••••••••••••• 285 P.G. Gervasi, P. Puccini, V. Longo, and A. Lippi

Stereochemistry of the Microsomal Glutathione S-Transferase­Catalyzed Addition of Glutathione to Chlorotrifluoroethene in Isolated Rat Hepatocytes •••••••••••••••••••••••••••••• 289 Sally J. Hargus, Michael E. Fitzsimmons, and M.W. Anders

ix

x

The Pathophysiological Significance of Reactive Oxygen Formation in Rat Liver ••••••••••••••••••.••.••••••.•••. 295 Hartmut Jaeschke, Arthur E. Benzick, Charles V. Smith, and Jerry R. Mitchell

Oxidative Stress During Hypoxia in Isolated-Perfused Rat Heart .••.••••.•••••••••••••.•••••••••••..••.•••• 299 James P. Kehrer, and Youngja Park

Alteration of Growth Rate and Fibronectin by Imbalances in Superoxide Dismutase and Glutathione Peroxidase Activity ••••••••••••••••••.••••.••.•••••.••. 305 Michael J. Kelner, and Richard Bagnell

The Antidotal Activity of the Thiol Drug Diethyldithiocarbamate Against N-Acetyl-p-Benzoquinone Imine in Isolated Hepatocytes ••••..•••••.••••••••.••••••••••.••.•••••• 311 Veronique V. Lauriault, and Peter J. O'Brien

Two Classes of Azo Dye Reductase Activity Associated with Rat Liver Microsomal Cytochrome P-450 ....•..•.......•.•••.•• 315 Walter G. Levine, and Shmuel Zbaida

Expression of a cDNA Encoding Rat Liver DT-Diaphorase in Escherichia Coli ••••••.•••.•.•....•.•••..••..•...••.•• 323 Qiang Ma, Regina Wang, Anthony Y.H. Lu, and Chung S. Yang

Suicidal Inactivation of Cytochrome P-450 by Halothane and Carbon Tetrachloride ..•••............•....•..••.•.•.•• 329 Maurizio Manno, Michela Rezzadore, and Stefano Cazzaro

Structure-Activity Relationships of Acrylate Esters: Reactivity Towards Glutathione and Hydrolysis by Carboxylesterase In Vitro ••.••••••••••••••••••.•••••••••• 333 T.J. McCarthy, and G. Witz

Glutathione Conjugates of Hydralazine Formed in Theperoxidase/Hydrogen Peroxide/Glutathione System •...••••..•..•.......••.....•........•.....•• 337 Larry G. McGirr, and Peter J. O'Brien

Contribution of 3,4-Dichlorophenylhydroxylamine in Propanil-Induced Hemolytic Anemia ..•.••..•..•••..••••.••. 343 David C. McMillan, Timothy P. Bradshaw, JoEllyn M. McMillan, Jack A. Hinson, and David J. Jollow

A Reduction in Mixed Function Oxidases and in Tumor Promoting Effects of Ethanol in a NDEA-Initiated Hepatocarcinogenesis Model ..••.....•..•.•...•..•...•.•• 347 Siraj I. Mufti, and 1. Glenn Sipes

Selective Inducers of the Coh-Locus Enhance the Metabolisms of Coumarin- and of Quinoline-Derivatives But Not That of Naphthalenes ....•....••..•••...•.....•....•••• 353 K.J. Netter, B. Hahnemann, S.A. Mangoura, F. Feil, M. Tegtmeier, R.T. Mayer, and W. Legrum

Primaquine-Induced Oxidative Stress in Isolated Hepatocytes as a Result of Reductive Activation ..•....••..••..••....••••• 359 Jose M. Silva, and Peter J. O'Brien

Nitroprusside: A Potpourri of Biologically Reactive Intermediates •.......••••••••••••••••••••••••••••.••• 365 Roger P. Smith, Dean E. Wilcox, Harriet Kruszyna, and Robert Kruszyna

Denitrosation of N-Nitrosodimethylamine in the Rat In Vivo ••••••••••• 371 Anthony J. Streeter, Raymond W. Nims, Pamela R. Sheffels, and Larry K. Keefer

Effect of Phenol and Catechol on the Kinetics of Human Myeloperoxidase-Dependent Hydroquinone Metabolism .••••••.•......•....•.•••.•..•••••.•.•.••. 377 Vangala V. Subrahmanyam, Prema Kolachana, and Martyn T. Smith

Activation of 1-Hydroxymethylpyrene to an Electrophilic and Mutagenic Metabolite by Rat Hepatic Sulfotransferase Activity ••••.••••••••••••••••••••••.•••• 383 Young-Joon Surh, Judith C. Blomquist, and James A. Miller

Bioactivation of 2,6-Di-Tert-Butyl-4-Methyl Phenol (BHT) and Hydroxylated Analogues to Toxic Quinoid Metabolites .•••..••••.•••••••••••••..•••••••.•••••••• 393 John A. Thompson, Judy L. Bolton, Kathleen M. Schullek, and Hubert Sevestre

Further Evidence for the Role of Myeloperoxidase in the Activation of Benzo[A]Pyrene-7 ,8-Dihydrodiol by Poly morpho-Nuclear Leukocytesm ...•.......••••.•..••.•.• 399 A. Trush, R. L. Esterline, W. G. Mallet, D. R. Mosebrook, and L. E. Twerdok

Quinones and Their Glutathione Conjugates as Irreversible Inhibitors of Glutathione S-Transferases •.••••••••••••••••••• 403 Ben van Ommen, Jan J.P. Bogaards, Jan Peter Ploemen, J. van der Greef, and Peter J. van Bladeren

Cytochrome P450 IA2 Activity in Man Measured by Caffeine Metabolism: Effect of Smoking, Broccoli, and Exercise .••...•••..•.•.•...••••.•••••.•.••..•.•.• 407 K. Vistisen, S. Loft, and H.E.Poulsen

Tissue Difference in Expression of Cytochrome P-450 Between Liver and Lung of Syrian Golden Hamsters Treated with 3-Methylcholanthrene •..••.•.•••••••••••.•••• 413 Hiroshi Fujii, Ikuko Sagami, Tetsuo Ohmachi, Hideaki Kikuchi, and Minro Watanabe

SESSION VII - XII

Role of Calcium in Toxic and Programmed Cell Death .•••••••••••••.• 419 Sten Orren ius, David J. McConkey, and Pierluigi Nicotera

Molecular Mechanisms of y-Diketone Neuropathy .•.•••••.••.••••••• 427 Doyle G. Graham, Mary Beth Genter St. Clair, V. Amarnath, and Douglas C. Anthony

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Microtubule Assembly Is Altered Following Covalent Modification by the n-Hexane Metabolite 2,5-Hexanedione •••.•••••..••••....•••••...•..•••••••• 433 Kim Boekelheide, Julia Eveleth, M. Diana Neely, and Tracy M. Sioussat

The Role of Hepatic Metabolites of Benzene in Bone Marrow Peroxidase-Mediated Myelo- and Genotoxicity •••••.•.•.••.••• 443 George Kalf, Robert Shurina, John Renz, and Michael Schlosser

Glutathione Conjugation as a Mechanism of Targeting Latent Quinones to the Kidney •.•••..••••..•.••.•••..•.••• 457 Serrine S. Lau, and Terrence J. Monks

Hepatic Bioactivation of 4-Vinylcyclohexene to Ovotoxic Epoxides .•••••••.••.....•...••..••••••••••••• 465 Bill J. Smith, Donald R. Mattison, and I. Glenn Sipes

Testicular Metabolism and Toxicity of Halogenated Propanes ••.•.••..•.............••........•.••••••••. 471 E. Dybing, E.J. Soderlund, M. Lag, G. Brunborg, J.A. Holme,J.G. Omichinski, P.G. Pearson, and S.D. Nelson

Lung Vascular Injury from Monocrotaline Pyrrole, a Putative Hepatic Metabolite ...•...•.................•... 477 Robert A. Roth, and James F. Reindel

Reactive Oxygen Species in the Progression of

xii

CCl4-Induced Liver Injury ..........•.....•..........•.•. 489 I.G. Sipes, A.E. EI Sisi, W.W. Sim, S.A. Mobley, and D.L. Earnest

Parenchymal and Nonparenchymal Cell Interactions in Hepatotoxicity ..........•••.•....•...••...•••..•••. 499 Debra L. Laskin

Signal Paths and Regulation of Superoxide, Eicosanoid, and Cytokine Formation in Macrophages of Rat Liver .••••...••.....••....•....•...•••....•.•.•• 507 Karl Decker

Reactive Metabolites from N-Nitrosamines .•..•••.••.•.••....•.•.. 521 Michael C. Archer, Jamie R. Milligan, Sandra Skotnicki, and Shi-Jiang Lu

Bisfuranoid Mycotoxins: Their Genotoxicity and Carcinogenicity •..••...•.....•••....••..•....••.•...• 525 Dennis P. H. Hsieh, and David N. Atkinson

Covalent Bonding of Bay-Region Diol Epoxides to Nucleic Acids •••...•••.....•••••••••••••••••••••••••. 533 Donald M. Jerina, Anju Chadha, Albert M. Cheh, Mark E. Schurdak, Alexander W. Wood, and Jane M. Sayer

Electrophilic Sulfuric Acid Ester Metabolites of Hydroxy-Methyl Aromatic Hydrocarbons as Precursors of Hepatic Benzylic DNA Adducts In Vivo •••••••••••••••••••••••••••• 555 James A. Miller, Young-Jooh Surh, Amy Liem, and Elizabeth C. Miller (deceased)

Heterocyclic Amines: New Mutagens and Carcinogenes in Cooked Foods ...•.•.•.•••••••••.•••.••••• 569 Takashi Sugimura, and Keiji Wakabayashi

Acetaminophen and Protein Thiol Modification ••.•..•••.••.•.•••••• 579 Sidney D. Nelson, Mark A. Tirmenstein, Mohamed S. Rashed, and Timothy G. Myers

Formation and Reactivity of a Quinone Methide in Biological Systems •...••....•......•.....••.•..••..•• 589 David Thompson, and Peter Moldeus

Mechanisms for Pyrrolizidine Alkaloid Activation and Detoxification •....•....•..•....•.•..........•..•• 597 Donald R. Buhler, Cristobal L. Miranda, Bogdan Kedzierski, and Ralph L. Reed

Sulfur Conjugates as Putative Pneumotoxic Metabolites of the Pyrrolizidine Alkaloid, Monocrotaline •.••••.•••..•.••.••• 605 R. J. Huxtable, R. Bowers, A. R. Mattocks, and M. Michnicka

The Metabolism of Benzene to Muconic Acid, A Potential Biological Marker of Benzene Exposure ...•.•.•••••••.•.•..•• 613 G. Witz, T.A. Kirley, W.M. Maniara, V.J. Mylavarapu, and B.D. Goldstein

Lessons on the Second Cancers Resulting from Cancer Chemotherapy ...•.•.••.•.•.•.•........••...•.•.••..• 619 Bernard D. Goldstein

Genetic Polymorphism of Drug Metabolism in Humans .••••••••••••••• 627 A.S. Gross, H.K. Kroemer, and M. Eichelbaum

Human Health Risk Assessment and Biological Reactive Intermediates: Hemoglobin Binding ....•.•••.••••.•.....••.• 641 L. Ehrenberg, and Margareta Tornqvist

Quantitating the Production of Biological Reactive Intermediates in Target Tissues: Example, Dichloromethane ••••.••..•.•.•••• 649 Richard H. Reitz

Trapping of Reactive Intermediates by Incorporation of l4C-Sodium Cyanide During Microsomal Oxidation •..•••••••••• 657 John W. Gorrod, Catherine M.C. Whittlesea, and Siu Ping Lam

Multiple Bioactivation of Chloroform: A Comparison Between Man and Experimental Animals .•.••.•.••••.•••..•.•..••.• 665 Luciano Vittozzi, Emanuela Testai, and Angelo De Biasi

xiii

SHORT COMMUNICATIONS

CCl4-Induced Cytochrome P-450 Loss and Lipid Peroxidation in Rat Liver Slices •.•.••••...••.•••.•••••••.. 669 Shana Azri, Heriberto P. Mata, A. Jay Gandolfi, and Klaus Brendel

Alteration of Benzo(A)Pyrene-DNA Adduct Formation by Rats Exposed to Simple Mixtures ...•.•.•••••••.•.•.•..•..• 675 S. Stephen Bentivegna, and Charlotte M. Witmer

Comparison of the Toxicity of Naphthalene and Naphthalene-1,2-Dihydrodiol (DIOL) •.••••.•••.•..•.•.•••.•• 681 R.E. Billings, N.E. Miller, J.E. Dabbs, S.E. LeValley, J.R. Hill, and C.E. Green

Selective Binding of Acetaminophen (APAP) to Liver Proteins in Mice and Men •........•.•..••••••.•......•.•• 685 Raymond B. Birge, John B. Bartolone, Charles A. Tyson, Susan G. Emeigh Hart, Steven D. Cohen, and Edward A. Khairallah

Post-Treatment Protection with Piperonyl Butoxide Against Acetaminophen Hepatotoxicity is Associated with Changes in Selective But Not Total Covalent Binding ......•.......•••.•.•.•.•••...••...••• 689 Joseph T. Brady, Raymond B. Birge1, Edward A. Khairallah, and Steven D. Cohen

Covalent Binding of a Halothane Metabolite and Neoantigen Production in Guinea Pig Liver Slices ••.•.•.•..•••• 693 Alan P. Brown, Kenneth L. Hastings, A. Jay Gandolfi, and Klaus Brendel

Extensive Alteration of Genomic DNA and Rise in Nuclear Ca2+ In Vivo Early After Hepatotoxic Acetaminophen Overdose in Mice .....•.•.•...•.•.•••.••••••••.•.•••.. 699 Sidhartha D. Ray, Christopher L. Sorge, Asadollah Tavacoli, Judy L. Raucy, and George B. Corcoran

The Possible Role of Glutathione on the Hepatotoxic Effect of Papaverine Hydrochloride In Vitro ....•.•.•••.•.•••• 707 Julio C. Davila, Daniel Acosta, and Patrick J. Davis

In Vivo and In Vitro Evidence for In Situ Activation and Selective Covalent Binding of Acetaminophen (APAP) in Mouse Kidney •.••......•.•.......•••.•••••••••.••••.• 711 Susan G. Emeigh Hart, Raymond B. Birge, Richard W. Cartun, Charles A. Tyson, Jack E. Dabbs, Ervant V. Nishanian, D. Stuart Wyand, Edward A. Khairallah, and Steven D. Cohen

Metabolism of Dichlorobenzenes in Organ Cultured Liver Slices .•.••..•...•.•.•.•.•••••••••.•.••.•••••••• 717 R. Fisher, S. McCarthy, I.G. Sipes, R.P. Hanzlik, and K. Brendel

Inhibition of Protein Synthesis and Secretion by Volatile

xiv

Anesthetics in Guinea Pig Liver Slices •••••••..•••••••.••••• 725 Hanan Ghantous, Jeannie Fernando, A. Jay Gandolfi, and Klaus Brendel

Dichlorobenzene Hepatotoxicity Strain Differences and Structure Activity Relationships .....•..•.••••••.••••••••• 731 Lhanoo Gunawardhana, and I. Glenn Sipes

The Use of 19F NMR in the Study of Protein Alkylation by Fluorinated Reactive Intermediates ••.••••••••••••..••.•• 735 James W. Harris, and M. W. Anders

S-Ethylthiotrifluoroacetate Enhancement of the Immune Response to Halothane in the Guinea Pig .•••••••.••.•..••.•• 739 Kenneth L. Hastings, Susan Schuman, Alan P. Brown, Cindy Thomas, and A. Jay Gandolfi

Bone Marrow DNA Adducts and Bone Marrow Cellularity Following Treatment with Benzene Metabolites In Vivo ••••••••••••••••••••••••••••••••••••••••••••• 745 Christine C. Hedli, Robert Snyder, and Charlotte M. Witmer

The Role of y-Glutamyl Transpeptidase in Hydroquinone-Glutathione Conjugate Mediated Nephrotoxicity .•..•....•..•.•••.••.••.•...•.•• 749 Barbara A. Hill, Herng-Hsiang Lo, Terrence J. Monks, and Serrine S. Lau

Cytochrome P450IIEl Metabolism of Pyridines: Evidence for Production of a Reactive Intermediate Which Exhibits Redox-Cycling Activity and Causes DNA Damage .•••••••..•••. 753 Sang Geon Kim, and Raymond F. Novak

Morphological Cell Transformation and DNA Adduction by Benz(J)Aceanthrylene and Its Presumptive Reactive Metabolites in C3HIOT1/2CL8 Cells ...•..•.•.•.•.••••••.••• 759 Jessica Lasley, Susan Curti, Jeffrey Ross, Garret Nelson, Ramiah Sangaiah, Avram Gold, and Stephen Nesnow

Covalent Binding of Oxidative Biotransformation Reactive Intermediates to Protein Influences Halothane-Associated Hepatotoxicity in Guinea Pigs ••.•••••....•••••.••.•..•••. 763 Richard C. Lind, and A. Jay Gandolfi

The Nephrotoxicity of 2,5-Dichloro-3-(Glutathion-S-YL)-1,4-Benzo­Quinone, and 2,5,6-Trichloro-3-(Glutathion-S-YL)-1,4-Benzoquinone Is Potentiated by Ascorbic Acid and AT-125 •••••••••••.••.•.••••••••••••••.••.••••••• 767 Terrence J. Monks, Serrine S. Lau, Jos. J. W. Mertens, Johan H.M. Temmink, and Peter J. van Bladeren

Generation of Free Radicals Results in Increased Rates of Protein Degradation in Human Erythrocytes Anne M. Mortensen, Melissa Runge-Morris, and Raymond F. Novak

Free Radicals Generated in Ethanol Metabolism May Be Responsible for Tumor Promoting Effects

771

of Ethanol •...•.•....•••.....•.•..•...••••••.•••••••• 777 Siraj I. Mufti

xv

Composition of Hepatic Lipids After Ethanol, Cod Liver Oil and Vitamin E Feeding in Rats •.•.•...••.•••.•.••.•.••• 785 Olalekan E. Odeleye, Ronald R. Watson, Cleamond D. Eskelson, and Siraj I. Mufti

Dietary Polyunsaturated Fatty Acid Promote Peroxidation and Its Possible Role in the Promotion of Cancer . • . . . • . . • • • . • • • . • • • • • • • • • • • • • • • • • • • . • . • . . • .• 789 Olalekan E. Odeleye, Ronald R. Watson, Cleamond D. Eskelson, and Siraj I. Mufti

Chiral Epoxides, Their Enantioselective Reactivity Towards Nucleic Acids, and a First Outline of a Quantum Chemical Structure-Reactivity Calculation .•...•.•..••.•.......•.•.. 793 H. Peter, B. Marczynski, D. Wistuba, L. V. Szentpaly, G. Csanady, and H.M. Bolt

Comparison of 8-Hydroxydeoxyguanosine and 5-Hydroxy-Methyluracil as Products of Oxidative DNA Damage ...•.•.••••. 801 David W. Potter, and Zora Djuric

Modulation of Aortic Smooth Muscle Cell Prolifertion by Dinitrotoluene .•....................••...•..•.••...... 805 K. Ramos, K. McMahon, C. Alipui, and D. Demick

Reactive Potential of Diethylstilbestrol Reactive Metabolites Towards Cellular Nuclear Proteins: Implications for Estrogen-Induced Carcinogenesis .....•..••.•..•.•.....•.•. 809 Deodutta Roy

Biochemical and Morphologic Response of Nasal Epithelia to Hyperoxia .........•.......•••....•••••.••.•••.•.•• 813 Patrick J. Sabourin, Kristen J. Nikula, Arnie J. Birdwhistell, Breton C. Freitag, and Jack R. Harkema

Membrane Stabilization as a Fundamental Event in the Mechanism of Chemoprotection Against Chemical Intoxication .•.••...••... 817 Howard G. Shertzer, Malcolm Sainsbury, and Marc L. Berger

Biochemical Eff.ects and Toxicity of Mitoxantrone in Cultured Heart Cells .....................•.....••.•.•.......•• 821 N.G. Shipp, and R.T. Dorr

Evidence for the Induction of an Oxidative Stress in Rat Hepatic Mitochondria by 2,3,7 ,8-Tetrachlorodibenzo-P-Dioxin (TCDD) ....••••..••••...•••.•.••••••••••••.•• 827 S.J. Stohs, N.Z. Alsharif, M.A. Shara, Z.A.F. AI-Bayati, and Z.Z. Wahba

Antioxidation Potential of Indole Compounds - Structure Activity Studies ....•............••..••.•..........•.• 833 M. Wilson Tabor, Eugene Coats, Malcolm Sainsbury, and Howard G. Shertzer

Measurement of Styrene-Oxide Cysteine Adducts in Hemoglobin

xvi

by Selective Catalytic Reduction ......•.....•..•.....•.... 837 David Ting, Martyn T. Smith, Penelope Doane-Setzer, Jeff Woodlee, and S. M. Rappaport

Studies on Biochemical Determinants of Quinone-Induced Toxicity in Primary Murine Bone Marrow Stromal Cells ••.•.•.••••••.••••.•••••••••.••.•.•••••• 843 Lorraine E. Twerdok, and Michael A. Trush

Selective Alteration of Cytokeratin Intermediate Filament by Cyclosporine A Is a Lethal Toxicity in PTK2 Cell Cultures •••••••••.•.•..•.••••.•..•.•..•••••••••• 847 Lawrence A. Vernetti, A. Jay Gandolfi, and Raymond B. Nagle

Rat Hepatic DNA Damage Induced by 1,2,3-Trichloropropane ...•••••.•••••••••••••••••.•••••. 853 Gregory L. Weber, and I. Glenn Sipes

Oxidation of Reduced Porphyrins by the Mitochondrial Electron Transport Chain: Stimulation by Iron and Potential Role of Reactive Oxygen Species ••••.•••.•..•••• 857 James S. Woods, and Karen M. Sommer

Future Research Needs for the Application of Mechanistic Data to Risk Assessment Donald J. Reed

863

Contributors ••••••••••••••••••••••••••••••••.•••••••••.•.• 869

Index 873

xvii