Biological Reactive Intermediates: Formation, Toxicity, and Inactivation

512 Pages·1977·19.908 MB·English

by  R. T. Williams (auth.), David J. Jollow, James J. Kocsis, Robert Snyder, Harri Vainio, Jussi Saukkonen, Charlotte Witmer, Thomas Walle (eds.)

Biological Reactive
Intermediates
Formation, Toxicity, and Inactivation
Biological Reactive
Intermediates
Formation, Toxicity, and Inactivation
Edited by
David J. Jollow
Medical University of South Carolina, Charleston
James J. Kocsis
Thomas Jefferson University, Philadelphia
Robert Snyder
Thomas Jefferson University, Philadelphia
and
Harri Vainio
Institute of Occupational Health, Helsinki
Associate Editors
Jussi Saukkonen and Charlotte Witmer
Thomas Jefferson University, Philadelphia
and
Thomas Walle
Medical University of South Carolina, Charleston
PLENUM PRESS· NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Main entry under title:
Biological reactive intermediates.
Includes bibliographical references and index.
1. Toxicology-Congresses. 2. Biotransformation (Metabolism)-Congresses. 3.
Carcinogenesis-Congresses. I. Jollow, David J. II. Turku, Finland Yliopisto.
[DNLM: 1. Biotransformation-Congresses. QV38 1603b 19751
RA1191.B56 615'.7'04 76-55724
ISBN 0-306-30970-X
Proceedings of an International Conference on Active Intermediates: Formation,
Toxicity, and Inactivation, held at the University of Turku, Turku, Finland, July
26-27,1975
© 1977 Plenum Press, New York
A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
All rights reserved
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 concept that detoxication is the inevitable result of biotransformation of
xenobiotic compounds by mammalian systems has undergone modification since
it was first described. Indeed, despite the fact that R. T. Williams popularized
the notion, he was among the first to caution that it was not possible to predict
the biological activities of the resulting metabolites. It has become increasingly
apparent in recent years that not only do many metabolites of drugs and other
chemicals display biological activity but also in many instances these metabolites
play an important role in initiating several forms of cancer and are the cause of a
variety of types of toxicity. Thus it seems appropriate to collect in one volume a
series of reports outlining advances in the study of the formation of chemically
active intermediary metabolic products of chemicals, mechanisms of toxicity or
carcinogenesis, and pathways for true detoxication of these chemicals.
The work of R. T. Williams, beginning in the late 1920s and early 1930s,
marked the first concerted effort to understand the biotransformation of foreign
chemicals in animals. He investigated the metabolic pathway of numerous
compounds in a wide variety of animal species while training large numbers of
our colleagues who have been responsible for further advances in biochemistry,
pharmacology, and toxicology. Another pioneer in the study of drug metabo
lism, B. B. Brodie, was unable to take part in this presentation, but his
significant contributions included not only laying the groundwork for the study
of human drug metabolism and pharmacokinetics but also teaching many of the
participants in this work. The fundamental contributions of H. Remmer to our
understanding of enzyme induction and cytochrome P450 as well as his vigorous
attempts to promote international scientific interchanges are also worthy of our
acclaim. Certainly no one has contributed more to our understanding of meta
bolic activation of xenobiotics and their covalent bonding to critical cellular
elements than J. A. and E. C. Miller. These workers were among the first to
demonstrate the metabolism of foreign compounds in vitro using liver mi
crosomal preparations, they were the first to demonstrate enzyme induction by
polycyclic aromatic hydrocarbons, and they have shown that many carcinogenic
and mutagenic chemicals undergo metabolism to reactive electrophilic inter
mediates that exert toxic effects by binding to critical sites on DNA, proteins,
and other macromolecules. We are fortunate in having all of these scientists
v
vi Preface
represented in this volume either directly or through their selected representa
tives and it is to them that we dedicate this book.
The papers published in this volume represent the proceedings of an inter
national conference entitled Active Intermediates: Formation, Toxicity, and
Inactivation which convened at the University of Turku, Turku, Finland, luly
26-27,1975. The conference was organized by a committee composed of Drs. 1.
F. Borzelleca, 1. R. Gillette, O. Hanninen, D. 1. lollow (Cochairman), 1. 1.
Kocsis, H. Remmer, R. Snyder (Cochairman), and H. Vainio (Cochairman). The
chairmen wish to express their deep appreciation to Dr. Gillette for his produc
tive efforts during the organization of the program.
The conference would not have been possible without the generous support,
encouragement, and participation of a number of individuals and organizations.
Among these were the National Institute of Environmental Health Sciences of
the National Institutes of Health, Professor K. Hartiala and the University of
Turku, the Turku University Foundation, the Ministry of Education of Finland,
Thomas lefferson University, Philadelphia, Pennsylvania, the Rohm and Haas
Company, the Hoffman-LaRoche Company, the Haskell Laboratories of E. I.
DuPont de Nemours and Company, and Laake Oy, Turku, Finland.
The editors decided not to present a verbatim reproduction of the discussion
that accompanied each group of papers presented at the conference. Instead,
Drs. 1. Saukkonen and C. M. Witmer of Thomas 1e fferson University and Dr. T.
Walle of the Medical University of South Carolina prepared summaries of the
discussions with the intent of presenting only their salient features in a concise
manner. We also wish to express our gratitude to Drs. R. T. Williams, K. 1.
Netter, 1. A. Miller, S. Orrenius, R. Sato, and H. Gelboin for their efforts as
session chairmen.
We wish to acknowledge the hospitality, the facilities, and the stimulating
scientific atmosphere that we enjoyed in Turku. International cooperation and
exchange of ideas should never be considered extraordinary. Communication is
the lifeblood of science. That our fundamental purpose can be achieved while
enjoying cordial relationships with our colleagues around the world is a fringe
benefit of untold value.
D.l.l.
1.1. K.
R.S.
H.V.
Contents
I. Reactive Intermediates in Toxicology and Carcinogenesis:
Role of Covalent Binding
1. Introduction to the Concept of Reactive Intermediates ............. 3
R. T. Williams
2. The Concept of Reactive Electrophilic Metabolites in Chemical
Carcinogenesis: Recent Results with Aromatic Amines, Safrole, and
Aflatoxin BI ............................................. 6
James A. Miller and Elizabeth C. Miller
3. Kinetics of Reactive Metabolites and Covalent Binding in Vivo and in
Vitro ................................................... 25
James R. Gillette
4. Biochemical Aspects of Toxic Metabolites: Formation, Detoxication,
and Covalent Binding ...................................... 42
David J. Jollow and Carole Smith
5. Discussion ............................................... 60
II. Formation of Reactive Intennediates
6. Mechanism of Microsomal Monooxygenases and Drug Toxicity ....... 65
Volker Ullrich
7. Discussion ............................................... 81
8. Aryl Hydrocarbon Hydroxylase: Induction ...................... 83
John B. Schenkman, Kathy M Robie, and Ingela Jansson
9. Discussion ............................................... 96
vii
viii Contents
10. Benzo [a] pyrene Metabolism: Enzymatic and Liquid Chromatographic
Analysis and Application to Human Liver, Lymphocytes, and
Monocytes ............................................... 98
Harry V. Gelboin, James Selkirk, Takao Okuda, Nobuo Nemoto, Shen
K. Yang, Friedrich 1. Wiebel, James P. Whitlock, Jr., Herbert J. Rapp,
and Robert C Bast, Jr.
11. Discussion ............................................... 124
12. Genetic Differences in Benzo [a] pyrene Carcinogenic Index in Vivo and
in Mouse Cytochrome PI 450·Mediated Benzo [a] pyrene Metabolite
Binding to DNA in Vitro .................................... 125
Daniel W. Nebert, Alan R. Boobis, Haruhiko Yagi, Donald M Jerina,
and Richard E. Kouri
13. Discussion .............................................. 146
14. Formation of Toxic Intermediates in Fetal Tissues ................ 148
Olavi Pelkonen
15. Discussion ............................................... 160
16. The Possible Role of Trout Liver Aryl Hydrocarbon Hydroxylase in
Activating Aromatic Polycyclic Carcinogens* .................... 162
Jorma T. Ahokas, Olavi Pelkonen, and Niilo T. Kiirki
17. Metabolic Activation of Methyldopa by Cytochrome P450-Generated
Superoxide Anion* ........................................ 167
E. Dybing, J. R. Mitchell, S. D. Nelson, and J. R. Gillette
18. Formation of Tertiary Amine N-Oxide and Its Reduction by Rat Liver
Microsomes* ............................................. 173
Ryuichi Kato, Hideyo Noguchi, Masahiko Sugiura, and Kazuhide
Iwasaki
III. Inactivation of Reactive Intermediates
19. Epoxide Hydratase: Purification to Apparent Homogeneity as a
Specific Probe for the Relative Importance of Epoxides among Other
Reactive Metabolites ....................................... 181
F. Oesch, P. Bentley, and H. R. Glatt
20. Glutathione S-Transferases .................................. 207
Donald M. Jerina and John R. Bend
*Poster sessions.
Contents ix
21. Discussion ............................................... 237
22. UDPGlucuronosyltransferase: Substrate Specificity and Reactivation
after Partial Separation from Other Membrane Components ......... 239
Osmo Hiinninen, Matti Lang, Ulla Koivusaari, and Tuula Ollikainen
23. Discussion ............................................... 250
24. Inactivation of Reactive Intermediates in Human liver ............. 251
Ham Vainio, Jukka Marniemi, Max Parkki, and Reijo Luoma
25. Discussion ............................................... 263
26. Nucleotide Pyrophosphatase as a Competitor of Drug Hydroxylation
and Conjugation in Rat Liver Microsomes . . ..................... 264
Eino Puhakainen
IV. Specific Reactive Intermediates
27. Metabolic Activation of Hydrazines to Highly Reactive Hepatotoxic
Intermediates ... _ -_. .............. _. ..................... 271
Jerry R. Mitchell, Sidney D. Nelson, Wayne R. Snodgrass, and John A.
Timbrel!
28. Discussion .............................. _. ............... 278
29. Activation of Nitrite ....................................... 279
William Lijinsky
30. Discussion ............................................... 284
31. Benzene Metabolism and Toxicity ............................. 286
R. Snyder, L. S. Andrews, E. W. Lee, C M. Witmer, M. Reilly, and J. J.
Kocsis
32. Benzene and p-Xylene: A Comparison of Inhalation Toxicities and in
Vitro Hydroxylations ...................................... 302
C Harper, R. T. Drew, and J. R. Fouts
33. Discussion ............................................... 312
34. Hepatotoxicity of Carbon Disulfide and of Other Sulfur-Containing
Chemicals: Possible Significance of Their Metabolism by Oxidative
Desulfuration ............................................ 314
Francesco De Matteis
x Contents
35. Studies of the Formation of Reactive Intermediates of Parathion ..... 320
Robert A. Neal, Tetsuya Kamataki, Marie Lin, Kay A. Ptashne, Ramesh
R. Dalvi, and Raymond E. Poore
36. Discussion ............................................... 333
37. Metabolism and Biological Activity of Benzo[a]pyrene and Its
Metabolic Products ........................................ 335
A. H. Conney, A. W. Wood, W. Levin, A. Y. H. Lu, R. L. Chang, P. G.
Wislocki, R. L. Goode, G. M Holder, P. M. Dansette, H. Yagi, and D.
M Jerina
38. Discussion ............................................... 357
39. Polycyclic Hydrocarbon Epoxides as Active Metabolic Intermediates .. 358
Peter Sims
40. Stereoselective Synthesis and Reactions of a Diol-Epoxide Derived from
Benzo[a] pyrene .......................................... 371
Donald M. Jerina, Haruhiko Yagi, and Oscar Hernandez
41. Discussion ............................................... 379
42. Additional Routes in the Metabolism of Phenacetin * .............. 380
Tilman Fischbach, Werner Lenk, and Dieter Sackerer
43. Biliary Metabolites of Paracetamol in Relation to Dose Level and
Various Pretreatments* ..................................... 387
A. Malnoe, M Strolin Benedetti, R. L. Smith, and A. Frigerio
44. Studies on Pharmacokinetics of N-Demethyldiazepam, the Active Main
Metabolite of Diazepam* ................................... 394
Lauri Kangas, Jussi Kanto, Raija Sellman, and Aimo Pekkarinen
V. Reactive Intermediates in Lipid Peroxidation
45. Regulation and Effects of Lipid Peroxidation in Isolated Hepatocytes . 401
Johan Hogberg
46. Discussion ............................................... 415
47. New Data Supporting an Obligatory Role for Lipid Peroxidation in
Carbon Tetrachloride-Induced Loss of Aminopyrine Demethylase,
Cytochrome P450, and Glucose-6-phosphatase ................... 417
Richard O. Recknagel, Eric A. Glende, Jr., and Andrew M.
Hruszkewycz
*Poster sessions.
Contents xi
48. Discussion ............................................... 429
49. Binding of Haloalkanes to Liver Microsomes ..................... 431
Hartmut Uehleke
50. Discussion ............................................... 446
51. Degradation of Cytochrome P450 Heme and Lipid Peroxidation in
Lead-Poisoned Rats* ....................................... 448
W. Penning and P. Scoppa
VI. Reactive Intermediates in Carcinogenesis
52. The Effects of Microsomal Enzymes on Chemical Oncogenesis in
Culture ................................................. 455
Stephen Nesnow and Charles Heidelberger
53. Discussion ............................................... 468
54. Role of Covalent Binding in Carcinogenicity ..................... 470
Peter Brookes
55. Discussion ............................................... 481
56. Interactions of Carcinogens with Human Cell DNA: Damage and
Repair .................................................. 483
James D. Regan
57. Discussion ............................................... 492
58. The Origin, Present Status, and Trends of Toxicology: A Review of the
Symposium in Turku, 1975 .................................. 493
Herbert Remmer
Participants ................................................. 499
Index ...................................................... 507