Table Of ContentGLUCOSE-6-PHOSPHAT E
DEHYDROGENAS E
Edited by
Akira Yoshida
Department of Biochemical Genetics
Beckman Research Institute of the City of Hope
Duarte, California
Ernest Beutler
Department of Basic and Clinical Research
Scripps Clinic and Research Foundation
La Jolla, California
1986
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Library of Congress Cataloging in Publication Data
Glucose-6-phosphate dehydrogenase.
Consists of lectures presented at an international
symposium held in Nov. 1985, under the auspices of the
National Institutes of Health and the City of Hope
National Medical Center.
Includes index.
1. Glucosephosphate dehydrogenase deficiency-
Congresses. 2. Glucosephosphate dehydrogenase—
Physiological effect—Congresses. I. Yoshida, Akira,
Date . II. Beutler, Ernest, Date . III. National
Institutes of Health (U.S.) IV. City of Hope National
Medical Center (U.S.) [DNLM: 1. Glucosephosphate
Dehydrogenase—metabolism—congresses.
2. Glucosephophate Dehydrogenase Deficiency—congresses.
QU 140 G567 1985]
RC632.G55G57 1986 616.3'9 86-45890
ISBN 0-12-772640-3 (alk. paper)
PRINTDE IN THE UNITDE STATSE OF AMERAIC
86 87 88 89 987654 3 2 I
PREFACE
Glucose-6-phosphat e dehydrogenas e (G6PD) was first found in red blood
cells and in yeast by Warbur g and Christia n in 1931. The enzyme is widely
distributed , from microorganism s to humans, and its discovery led to the
elucidation of the pentose-phosphat e pathway by some of the early giants of
biochemistry , including Lipmann , Dickens, Horecker , and Racker.
G6PD is a key enzyme in the generation of NADPH and in the productio n
of ribose-5-phosphate , a building block of nucleic acids. About 30 years ago, a
deficiency of G6PD activity in red blood cells of persons sensitive to the
hemolytic effect of the antimalaria l compound primaquin e was discovered.
G6PD deficiency was soon also found to be one of the causes of infection-
induced hemolysis, hereditar y nonspherocyti c hemolytic anemia, fava
bean-induce d hemolytic anemia, and, in some populations , severe neonatal
jaundice leading to kernicterus .
Many hematologists, geneticists, and biochemists found G6PD to be an in›
valuable tool to study a variety of fundamenta l biological problems. These
studies have greatly advanced our knowledge of genetics, evolution, molecular
structure , enzyme kinetics, and hormona l and nutritiona l regulation . Recogniz›
ing the need for a comprehensiv e conference on these diverse subjects related to
G6PD, an internationa l symposium on G6PD was held in November 1985,
under the auspices of the National Institute s of Health (HL-33787) and the City
of Hope National Medical Center. The participants , representin g a broad range
of expertise, reviewed the curren t scope of our knowledge, critically evaluated
previous studies, and discussed future studies of both the basic and practica l
aspects of the G6PD problem. This volume contains all of the lectures presented
by the participants . It is hoped that these proceedings will stimulate future
studies and bridge the gap between the disciplines.
We wish to acknowledge the contribution s of all participants , and the in›
valuable planning and editorial assistance of Dian De Sha and Anna Milne.
Akira Yoshida
Ernest Beutler
ix
Paul E. Carson(cid:151)I n Memoria m
Paul E. Carson was born in 1925 and passed away on May 25, 1985, in
Chicago. Dr. Carson was Professor and Chairma n of the Departmen t of Phar ›
macology and Senior Attending Physician at Rush-Presbyteria n St. Luke’s
Medical Center in Chicago.
Dr. Carson was a world-renowne d scientist, physician, and educator . His
pioneering studies on the toxicity of antimalaria l drugs led to the establishmen t
of better chemotherapeuti c agents and regimens against this scourge, and to
the discovery of hereditar y glucose-6-phosphat e dehydrogenas e deficiency.
The discovery of this condition, which affects millions of people throughou t
the world, in turn played a seminal role in the creation of the field of phar›
macogenetics.
In his distinguished career, Dr. Carson had served as Research Fellow and
Chief, Departmen t of Biochemistry for the Atomic Bomb Casualty Commission
in Japan (1950-1952); Physician and Scientist, Departmen t of Biochemistr y in
Brookhaven National Laborator y (1952-1955); and faculty member at the
University of Chicago (1955-1971). The recipient of a Research Career
Development Award, Dr. Carson had been honored with the Distinguished
Service Award from the Medical Alumni Association of the University of
Chicago. He was a member of many societies including the Centra l Society for
Clinical Research, the American Society for Human Genetics, and the
American Society of Clinical Pharmacolog y and Therapeutics . At the time of
his death, he was heavily engaged in elucidating the pharmacokinetic s of
8-aminoquinoline s and other antimalaria l compounds.
He is survived by his wife, Mary Carson of Chicago, a son, Jeffrey, and two
daughters , Jan and Amy.
xi
DRUG-INDUCED HEMOLYTIC ANEMIA AND NON-SPHEROCYTIC
HEMOLYTIC ANEMIA >12
Ernest Beutler
Scripps Clinic & Research Foundation
Department of Basic & Clinical Research
10666 North Torrey Pines Road
La Jolla, California 92037
Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was
discovered as an outgrowth of investigations of the hemolytic
effect of the antimalarial compound primaquine. The great
interest that the scientific community has manifested in this
enzyme deficiency over the past thirty years is due, in large
part, to the usefulness of this X-linked enzyme defect in a
variety of genetic studies. But a major portion of the interest
in G-6-PD deficiency must also be attributed to the fact that
this defect also has clinical consequences. These consequences
may vary in severity from a trivial shortening of the red cell
life span to life threatening hemolytic anemia or kernicterus in
1-This is publication number 4196 BCR from the Research
Institute of Scripps Clinic.
^This work was supported in part by Grant #HL 25552 from the
National Institutes of Health.
GLUCOSE-6-PHOSPHAT E Copyright ' 1986 by Academic Press, Inc.
DEHYDROGENASE 3 All rights of reproductio n in any form reserved.
4 Ernest Beutler
the newborn. It seems appropriate at the beginning of this
conference, therefore, to briefly review the clinical
manifestations of G-6-PD deficiency and to speculate how they
may come about.
I. DRUG INDUCED HEMOLYSIS
In the common, polymorphic forms of G-6-PD deficiency
hemolytic anemia occurs only when the erythrocyte is exposed to
certain stresses. Most G-6-PD deficient individuals with common
forms of G-6-PD deficiency such as G-6-PD A- and G-6-PD
Mediterranean go through life without ever being aware that they
are enzyme deficient. Their red cell life span is normal, or
nearly so, and the hemoglobin level of the blood is maintained
at normal levels.
The administration of certain drugs has the capacity to
alter this state. The prototype of drugs that precipitate
hemolytic episodes in G-6-PD deficiency is primaquine, but there
are many others that can also do so. Table 1 presents a list
of drugs which have been shown to precipitate hemolytic anemia
in G-6-PD deficiency.
The number of drugs that we now acknowledge to have
hemolytic potency is much smaller than was once thought (1,2).
Drug-Induce d and Non-Spherocyti c Hemolytic Anemia 5
Because G-6-PD deficiency was first discovered when the
administration of a drug produced hemolytic anemia, there was
initially a tendency to believe that hemolysis occurring in G-6-
PD deficient individuals was always due to drug ingestion.
TABLE 1. Drugs and chemicals that have clearly been shown to
cause clinically significant hemolytic anemia in G-6-PD
deficiency.
Acetanilid Phenylazodiaminopyridine
Methylene blue (pyridium)(3)
Nalidixic acid (Negram) Sulfanilamide
Naphthalene Sulfacetamide
Niridazole (Ambilhar) Sulfapyridine
Nitrofurantoin (Furadantin) Sulfamethoxazole (Gantanol)
Phenylhydrazine Thiazolesulfone
Primaquine Toluidine blue
Pamaquine Trinitrotoluene (TNT)
Pentaquine
Thus, any drug that had been taken prior to the onset of a
hemolytic episode was listed as one which might precipitate
hemolysis in G-6-PD deficient persons. It was realized only
later that other stresses could precipitate hemolytic anemia in
G-6-PD deficient individuals. Prominent among such factors was
infection, particularly bacterial pneumonias and typhoid fever
(1,4). In many cases it was presumably the stress imposed by
infection that had produced the hemolytic anemia and not the
drug at all. A list of drugs that were once thought to cause
6 Ernest Beutler
hemolytic anemia in G-6-PD deficiency but that are now known to
be innocuous is presented in Table 2.
Acetaminophen (paracetamol, Menapthone
Tylenol, Tralgon, p-Aminobenzoic acid
p-hydroxyacetanilide) Phenylbutaz one
Acetophenetidin (phenacetin) Phenytoin
Acetylsalicylic acid (aspirin) Probenecid (Benemid)
Aminopyrine (Pyramidon, Procaine amide
amidopyrine.) hydrochlor ide(Prones tyl)
Antazoline (Antistine) Pyrimethamine (Daraprim)
Antipyrine Quinidine
Ascorbic acid (vitamin C) Quinine
Benzhexol (Artane) Streptomycin
Chloramphenicol Sulfacytine
Chlorguanide (Proguanil, Sulfadiazine
Paludrine) Sulfaquanidine
Chloroquine Suifamerazine
Colchicine Sulfamethoxypyriaz ine
(Kynex)
Diphenylhydramine (Benedryl) Sulfisoxazole
(Gantrisin)
Isoniazide Trimethoprim
L-DOPA Tripelennamine
(Pyribenzamine)
Menadione sodium bisulfite Vitamin Κ
(Hykinone)
TABLE 2. Drugs that can probably be given safely in normal
therapeutic doses to G-6-PD deficient subjects (without
nonspherocytic hemolytic anemia).
Fava beans, too, have the capacity to precipitate hemolysis
in some G-6-PD deficient persons. This interesting type of
hemolytic anemia, designated as favism, will be discussed later
in this symposium.
Drug-Induce d and Non-Spherocyti c Hemolytic Anemia 7
II. MECHANISM OF HEMOLYSIS
In the many years that have passed since the hemolytic
effect of primaquine was first found to be due to G-6-PD
deficiency many studies have been carried out to clarify the
mechanism by which red cells are destroyed. Even now all the
details are not fully understood. The most likely mechanism is
that the generation of hydrogen peroxide and free radicals
damage hemoglobin and red cell components. Reduced glutathione
(GSH) acting through the enzyme glutathione peroxidase serves as
a scavenger for low levels of hydrogen peroxide. In the process
of removing hydrogen peroxide GSH is oxidized to glutathione
disulfide (GSSG). Red cells from G-6-PD deficient individuals
lack the capacity to regenerate GSH by reducing GSSG. Thus,
they are deprived of the protective effect of GSH and, in
addition, the accumulated GSSG may damage red cells. The
mechanism by which G-6-PD protects red cells against destruction
is schematically illustrated in Figure 1.
8 Ernest Beutler
6-PH0SPH0GLUC0N ATE GLUCOSE - 6 - Ρ
Fig. 1. A schema of the mechanism of protection of red
cells against peroxide by G-6-PD.
How the peroxide does its mischief is not entirely clear.
One mechanism may be the cross-linking membrane proteins (5).
We shall hear more about this later in this symposium. Peroxide
and free radicals may also result in denaturation of hemoglobin,
and their attachment to the membrane as Heinz bodies impedes the
passage of red cells through the narrow slits which separate the
splenic pulp from the sinuses (6).
