Free Radicals in Diagnostic Medicine: A Systems Approach to Laboratory Technology, Clinical Correlations, and Antioxidant Therapy

460 Pages·1994·20.34 MB·English

by  Kunio Yagi (auth.)

FREE RADICALS IN
DIAGNOSTIC MEDICINE
A Systems Approach to Laboratory
Technology, Clinical Correlations, and
Antioxidant Therapy
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NA THAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DA VID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
Recent Volumes in this Series
Volume 360
ARTERIAL CHEMORECEPTORS: Cell to System
Edited by Ronan G. O'Regan, Philip Nolan, Daniel S. McQueen, and David J. Paterson
Volume 361
OXYGEN TRANSPORT TO TISSUE XVI
Edited by Michael C. Hogan, Odile Mathieu-Costello, David C. Poole,
and Peter D. Wagner
Volume 362
ASPARTIC PROTEINASES: Structure, Function, Biology, and Biomedical Implications
Edited by Kenji Takahashi
Volume 363
NEUROCHEMISTRY IN CLINICAL APPLICATION
Edited by Lily C. Tang and Steven J. Tang
Volume 364
DIET AND BREAST CANCER
Edited under the auspices of the American Institute for Cancer Research;
Scientific Editor: Elizabeth K. Weisburger
Volume 365
MECHANISMS OF LYMPHOCYTE ACTIVATION AND IMMUNE REGULATION V:
Molecular Basis of Signal Transduction
Edited by Sudhir Gupta, William E. Paul, Anthony DeFranco, and Roger Perlmutter
Volume 366
FREE RADICALS IN DIAGNOSTIC MEDICINE: A Systems Approach to Laboratory
Technology, Clinical Correlations, and Antioxidant Therapy
Edited by Donald Armstrong
Volume 367
CHEMISTRY OF STRUCTURE-FUNCTION RELATIONSHIPS IN CHEESE
Edited by Edyth L. Malin and Michael H. Tunick
Volume 368
HEPATIC ENCEPHALOPATHY, HYPERAMMONEMIA, AND AMMONIA TOXICITY
Edited by Vicente Felipo and Santiago Grisolia
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume
immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact
the publisher.
FREE RADICALS IN
DIAGNOSTIC MEDICINE
A Systems Approach to Laboratory
Technology, Clinical Correlations, and
Antioxidant Therapy
Edited by
Donald Armstrong
State University of New York at BuffaJo
BuffaJo, New York
SPRINGER SCIENCE+ BUSINESS MEDIA, LLC
Library of Congress Cataloging in Publication Data
On file
Proceedings of an International Symposium on Free Radicals in Diagnostic Medicine: A Systems Approach
to Laboratory Technology. Clinical Correlations. and Antioxidant Therapy.
held October 7-9. 1993. in Buffalo. New York
ISBN 978-1-4613-5742-1 ISBN 978-1-4615-1833-4 (eBook)
DOI 10.1007/978-1-4615-1833-4
© 1994 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1994
Softcover reprint of the hardcover 1s t edition 1994
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
permis sion rrom the Publisher
ACKNOWLEDGEMENTS
Support from the following sponsors are gratefully acknowledged:
MAJOR CORPORATE SPONSORS
Marion Merrell Dow
Institute de Recherches Internationales Servier and Servier
International, France
Eastman Kodak Company, Clinical Products Division
La Haye Laboratories, Inc.
DDI Pharmaceuticals, Inc.
Upjohn Laboratories, Clinical Research Division
Research Institute on Addictions
Sanofi winthrop Pharmaceuticals
Roche Diagnostic Systems, Inc.
Pfizer Pharmaceutical Company
Otsuka America Pharmaceutical Company
Ono Pharmaceutical Company, Japan
Merck & Company, Inc., Human Health Division
Hoffman LaRoche, Inc.
The Henkel Corporation, Fine Chemicals Division
Hamamatsu Photonics Systems, Japan
Eisai Company, Ltd., Japan
Cayman Chemical Company
Boehringer Mannheim Corporation
3M Pharmaceuticals
Clinico PharmacoKinetics Laboratory, The Millard Fillmore Hospital,
Buffalo, NY
OTHER CORPORATE SPONSORS
Empire Imaging Systems
FRESA BioMedical Laboratories, Inc.
JM Science, Inc.
Miles, Inc., Diagnostic Division
Shimadzu Scientific Instruments, Inc.
S1M - American Instruments and Milton Roy Company
Roswell Park Cancer Institute
VERIS Vitamin E Research and Information Science
ORGANIZATIONS
University at Buffalo
Roswell Park Cancer Institute
American Association of Clinical Chemistry, Upstate NY Section
The Organizing Committee wishes to thank G. Alan Stull, Dean of the
School of Health Related Professions, University at Buffalo and James
Karr, Chief of the Office of Scientific Administration, at Roswell Park
Cancer Institute for their introductory remarks on the relevance and
timeliness of this topic and to the following individuals who graciously
gave of their time to serve as Moderators of the various sessions:
Harold Box, Ph.D., Chairman, Department of Biophysics, Roswell Park
Cancer Institute; David Hohnadel, Ph.D., President, National Academy of
Clinical Biochemistry; Joseph IZzo, M.D., Chairman, Department of
Medicine, The Millard Fillmore Hospitals and University at Buffalo;
v
Gerald Louge, M.D., Chief of Staff, The Veterans Administration Medical
Center of Buffalo; John Naughton, M.D., Vice President for Clinical
Affairs and Dean of the School of Medicine and Biomedical Sciences,
University at Buffalo; Kyu Shin, M.D., Chief of Radiation Medicine,
Roswell Park Cancer Institute; John Wright, M.D., Chairman, Department of
Pathology, University at Buffalo and Lloyd Horrocks, Ph.D., Department of
Biochemistry, The Ohio State University and Editor of the Journal of
Molecular and Cellular Neurochemical Pathology. We also extend our
special appreciation to Richard Stockton, Ph.D., Gail Bersani and Arthur
Michalek, Ph.D. and Debbie Holden for assistance with other
organizational matters, to LuAnn Kaite and Debbie Murello for typing and
their help with numerous details before, during and after the Symposium
and to Marion Merrell Dow, Inc. for a generous educational grant to
produce the conference program and abstract booklet. The University at
Buffalo Health Science Library, serving as a resource for the Middle
Atlantic Region of the National Network Libraries and Medicine, provided
a MEDLINE search for participants.
PREFACE
An International Syaposiua on Free Radicals in Diagnostic Medicine was
co-sponsored by the state University of New York at Buffalo, Roswell Park
Cancer Institute, and the Upstate NY Section of the American Association
of Clinical Chemistry. The theme was "A Systems Approach To Laboratory
Technology, Clinical Correlations And Antioxidant Therapy." The
symposium was held on October 7-8, 1993 at the Hyatt Hotel and on October
9 at Roswell Park Cancer Institute, Buffalo, New York. This proceedings
volume contains chapters from platform presentations, poster sessions and
from invited special lectures in the areas of basic science, clinical
applications and efficacy of treatment.
A Special Lecture on the relevance of free radical analysis to clinical
medicine was presented by Professor Kunio Yagi of Japan. The Yagi
procedure to measure thiobarbituric acid (TBA) reaction reflects the
amount of reactive substances, lipid peroxides and aldehydes, in the
sample. For example, normal subjects will have less than 4 nmol/ml of
serum lipid peroxides, while a person with diabetes generally has equal
or greater than 5.0 and a diabetic person with vascular complications
often exceeds 7.5 nmol/ml. Serum TBA is a clinically important measure
that relates to aging, gender and estrogen as an antioxidant, in the
prognosis for vascular disorders, and in pathological conditions relative
to the amount of lipid peroxidation.
The BASIC SCIENCES portion of the program examined: "Mechanisms of
Action, Pathophysiology and Laboratory Tests" in six presentations.
Free radicals in normal physiology, phagocytosis and necrosis was
presented by Professor Mary Treinen Moslen who emphasized that free
radicals are continually formed in biology and most abundantly by the
mitochondrial-electron transport chain reactions. Free radical
generation is enhanced by radiation, inflammation, and by the ischemic
reperfusion process. Three stages identified are: initiation,
detoxification and membrane propagation reactions, and decomposition of
membrane into smaller aldehydes.
Chromosomal damage in Bloom's Syndrome was examined by Professor Thomas
Nicotera as a cellular model to study chronic superoxide anion stress.
Hypotheses were raised of cells deficient in enzyme activities to
detoxify superoxide and/or overprotection of superoxide radical.
Clinical correlates are seen in: neoplasia, neurologic disease, short
stature, sensitivity to sunlight and predisposition to diabetes.
Professor Donald Armstrong presented an analysis of free radicals and
related compounds in the clinical laboratory. He emphaSized that it is
nearly impossible to read the literature today without finding
involvement of oxidative stress and oxygen free radical (OFR) generation.
Dr. Armstrong gave a detailed presentation of assays and methodologies
within the province of the modern hospital clinical laboratory to
approach the quantitation of free radical biology status and the
numerical documentation of oxidative stress. Thus, clinical laboratories
have an important role in the application of free radical measurement
methods.
State of the art of free radical testing was discussed by Dr. Charles
Pippenger. Enzymes relating to OFR generation and antioxidant defense
vii
systems are present in a wide variety of tissues and reflect genetic
characteristics; their levels are modified by environmental and disease
factors. Laboratory quality control and standards were emphasized with
recognition of a certain biologic variability. This type of clinical
laboratory data applied to population studies can be utilized as
information to improve health care. Examples include: (1) Ashkenazi Jews
carry low SOD levels, (2) OFR mediated disease precursor that takes years
to develop may be present in "normal" populations, and (3) after 60 years
of age, OFR scavenging enzymes decline even with vitamin
supplementation.
In comment, Professor Joseph L. Izzo, Jr. Chairman of this session,
observed that there will be resistance to reimbursement of OFR clinical
laboratory studies until we demonstrate that the test result alters
therapy and physician decision making behavior to change what we do for
the patient.
Two CLINICAL SCIENCE sections addressed organ specific disorders and
systeaic invo1veaent. Dr. Domenico Pellegrini-Giampietro began with a
talk on Neurological Disease. The brain is vulnerable to OFR damage
because it: (1) has 1/5 of cardiac output, (2) is lipid rich, (3) poor
in catalase activity, and (4) several areas of brain are rich in iron but
cerebral spinal fluid transferrin is low. Radical production is
associated with many neurologic diseases including: Parkinson's, tardive
dyskinesia, Schizophrenia, Down's and Alzheimer's. OFR production is
linked to glutamate receptor excitation. If a molecule can be designed
that is a glutamate receptor antagonist and also has scavenger properties
this would be useful to prevent neuronal cell death in ischemia.
Ocular Disease was presented by Professor Robert Anderson. Cataracts,
retinopathy, light damage, age-related macular degeneration (ARMO) are
all OFR associated. Lens clarification depends on maintaining a reducinq
environment. Cigarette smoking increases cataract risk (there are 1017
radicals in one puff of a cigarette). High oxygen levels may damage the
retina and this is of special concern in pre-term infants who are
deficient in vitamin E (with 10% of full term levels). With aging there
is a greater susceptibility to OFR damage. ARMO is the leading cause for
blindness in persons over 50 years of age.
Endocrine Disease was discussed by Professor Paresh Dandona who in
discussing thyroid hormone experiments raised the precautionary note that
in vitro chemistry data may show striking differences from in vivo
biological data. For example, an in vitro antioxidant may cause
increased oxygenation in vivo through metabolic and other factors. In
commenting on other diseases he noted that diabetics have much higher 8-
hydroxy quanosine (4 to 5 x) than normal controls and also greater DNA
damage in mononuclear cells. Oophorectomy increases OFR levels and
estrogen hormone replacement therapy (HRT) decreases OFR levels. When
small amounts of endotoxin (4ng/kg) are given to volunteers there is an
increased plasma TNF alpha and IL-6, and increased OFR generation by
chemiluminescence not withstanding a concomitant increased glucocorticoid
level.
Cutaneous Disease was discussed by Professor Alice Pentland to complete
the first of the three-day symposia. This presentation dealt with oxygen
free radicals (OFR), the electromagnetic spectrum, clinical
considerations, photochemistry and molecular aspects of tissue injury and
repair.
Cardiac Disease was presented by Professor Roberto Ferrari. This
presentation included discussion of defenses against OFR toxicity,
sources of OFR, detection and oxidative damage. Problems relating to
measurements (indices) of oxidative stress in the clinical setting were
discussed together with the need for more specific data and knowledge to
most effectively conduct clinical therapy trials.
Vascular Disease was presented by Professor Peter Reaven who examined the
role of oxidized low density lipoprotein (LDL) together with the
dynamic/kinetic dimensions they activate which leads to cytokine release,
macrophage accumUlation, passage of LDL through the endothelial barrier
and finally to endothelial cell damage and plaque formation. This
presentation also examined factors that affect LDL oxidation and
discusses methodologies to determine in vivo oxidation.
viii
Hemolytic Disease was the subject of the presentation by Professor Edward
J. Lesnefsky, Jr. This discourse looked at clinical syndromes, target
organs, and examined in substantial detail the two categories of iron
pools: (1) transferrin bound and (2) non-transferrin pool bound to
ammonium citrate. The former is non-toxic and the latter produces
disease since iron is insoluble without ligand. Organ dysfunction,
increased susceptibility to ischemia-reperfusion injury and methods of
therapy by phlebotomy, chelation and antioxidants were also discussed.
Infertility was discussed by Professor Claude Gagnon who presented the
role of reactive oxygen species (ROS) in male infertility. The mode of
action of ROS was outlined and a series of experiments examining both
beneficial and detrimental aspects of ROS on spermatozoa was covered.
Toxic levels of ROS reduce sperm function and fertility. Yet ROS has
beneficial effects to produce capacitated activity (CA) or hyperactivity
(HA) giving zigzag movement to sperm and greater torque, thus greater ova
membrane penetration. Leukocytes in the vagina do harm and are one cause
for infertility.
Renal Disease and reactive oxygen species contribution was presented by
Professor Leonard Feld with both common features and differences
emphasized among clinical syndromes. Resident cell populations
(mesangial, endothelial, epithelial) and infiltrating cells (neutrophils,
macrophages, platelets) may be involved at different renal sites
(vascular, glomerular, tubular). Three models to study renal disease
are: (1) anti-glomerular basement membrane (anti-GBM) which features
proteinuria and beneficial effects of catalase and disferoxamine but not
DMSO, and (2) membranous glomerulonephritis with decreased proteinuria
from DMTU and DMSO but not catalase or SOD which suggest that hydroxyl
radical is involved, and (3) puromycin nephrosis in which hypoxanthine
is an intermediate step in ROS injury. Allopurinol and SOD reduce the
injury but not catalase or DMSO. Free radicals in one form or another
are important in each renal disease state.
Liver, Pancreas and Gastric Disease were reviewed by Professor Kunio Yagi
to wrap-up the second day'S platform presentations. One can identify
gastric mucosal injury associated with a rise in plasma thiobarbituric
acid (TBA). An experimental preparation with infusion of hypoxanthine
and oxygen caused detectable mucosal injury and increased TBA. Better
protection is obtained by SOD plus catalase than cimetidine and H-2
receptor blocker.
THE CLINICAL SCIENCES II SESSIONS on Systemic Involvement addressed:
Autoimmune Disease which was presented by Professor Jonathan Leff who
commented on markers of oxidative damage in conditions such as sepsis,
ARDS, AIDS, rheumatoid arthritis, hepatitis, congestive heart failure and
hemolytic anemia. Polarographic catalase assay, superoxide dismutase
(MnSOD) assay which is elevated prior to development of ARDS, breath
hydrogen peroxide, lipid peroxide products present in blood or synovial
fluid of particular relevance to rheumatoid arthritis, and reduced levels
of serum antioxidants for example in AIDS were discussed.
Cancer and Chemotherapy was presented by Professor Peter O'Brien who
discussed mechanisms by which dietary and natural antioxidants have anti
carcinogenetic actions. All antioxidants inhibit P-450 enzyme systems.
categories of effects include: precursor, blocking and suppressors.
Dietary constituents mentioned were: flavenoids in fruits and vegetables,
medicinal plants, green tea, garlic, onions, leaks, strawberries,
cabbage, etc.
Free radical induced drug reactions was addressed by Dr. Charles
Pippinger who focused on idiosyncratic drug reactions (lOR) which appear
to be related to and controlled by genetic a profile. Specific examples
include: adriamycin toxicity, valproic acid and acute hepatiC toxicity
in children under 10 years, and halothane malignant hyperthermia. He
brought out the concept of free radical deficiency and risk for disease.
Markers for clinical laboratories are needed to identify and prevent
potential IDR.
ix
Shock and Multiple Organ Dysfunction Syndrome (MODS) was presented by
Professor Patricia Abello who brought together a coordinated presentation
which connected clinical events, trigger mechanisms, acute phase
responses, with the interactions and consequences of OFR. MODS is the
leading cause of death in Critical Care Units. Gene expression results
in acute phase and heat shock responses. In sepsis hypermetabolism
precedes MODS. It is important to understand extracellular (eg.,SOD,
catalase) from intracellular (e.g., DMSO, allopurinol) protective
mechanisms and agents.
Alcoholism and fetal alcohol syndrome was presented by Professor Consuelo
Guerri who commented on mechanisms of alcohol-induced free radical (FR)
formation and discussed pathways involving the cytosol, cellular
fractions and the cytochrome P-450 system. The role of acetaldehyde in
ethanol-induced FR production, the effects of liver anti-oxidants and
oxidative stress were commented on. The fetal alcohol syndrome includes:
metabolic effects, astrocyte development impairment and mental
retardation.
Oxidative stress and aging was presented by Dr. Richard Cutler who
discussed this topic in terms of: 1) the problem that humans may be
living longer than genetically programmed with advances in life span
compared to previous periods over past 50,000 years, 2) organ function
peaks at the onset of sexual maturity and underpoes a steady rate of
decline thereafter, 3) elimination of major causes of death effects
aging. and 4) comparative life spans in nature and models that correlate
oxidative stress and antioxidant defense mechanisms.
THERAPEUTIC INTERVENTIONS: Inhibitors of Pree Radical Reactions.
vitamin B - Professor Jeffrey Blumberg. There are age-related changes to
decrease immune mechanisms such as T-cell responses which translates to
a greater incidence of infectious disease and risk of morbidity and
mortality. Vitamin E improves the immune response index. There is
evidence of vitamin E deficiency in certain elderly populations.
Gliclazide - Professor Paul Jennings. Diabetes Mellitus is associated
with cardiovascular complications in which prevalence correlations with
duration of disease. Therapeutic strategies to prevent premature death
include: diet, exercise, no smoking, and glucose control. Gliclazide
(glyburide), a sulfonyl urea, increases insulin secretion by ~ cell and
decreases platelet adhesiveness; the actions decrease platelet
aggregation, increase tissue plasminogen activator (tPA) and
fibrinolysis, decrease oxidative stress and lipid peroxidation.
Beraprost and aminoguanide - Professor Paresh Dandona. The culprit cell
in the atherosclerotic plaque is the monocyte that undergoes adhesion and
penetration into the vascular wall, imbibes oxidized low-density
lipoprotein (LDL), is transformed into the foam cell with capacity for
excreting reactive materials; this forms the fatty streak. A further
stage of endothelial damage will result in the beginning of a mural
thrombus. Oxidation of LDL is a calcium - dependent process. Beraprost
and Aminoguanidine are inhibitory to free radical generation. LDL
oxidation is inhibited by Aminoguanidine. Clinical trials are in
progress to test the potential beneficial effects of these drugs.
Carotenoids and other Vitamins - Dr. Wolfgang Schalch. There is
epidemiological evidence for cardiovascular disease risk reduction
associated with increased dietary carotene; 30% decrease in coronary
heart disease risk (NEJM 328;1450,1993), and 50% decrease in major
cardiovascular events (Circ. Supplement 82: 111 -201, 1990). There is
also potential mechanism of cancer risk reduction and decreased
cataracts. In China a Nutrition International Trial with B carotene,
vitamin E and selenium was initiated (J. National Cancer Institute 85:
1483 - 92, 1993).
Flavenoids Professor Elliott Middleton. At low concentrations
flavenoids affect mitogenesis, secretory function, and inflammatory
cells. Secretagogues stimulating histamine can be inhibited by
flavenoids; they also have scavenger activity against the hydroxyl and
the lipid peroxide radicals. Protection against free radical damage
x