Glucuronic Acid Free and Combined. Chemistry, Biochemistry, Pharmacology, and Medicine

631 Pages·1966·7.95 MB·English

by  Geoffrey Dutton (Eds.)

Contributors
J. J. BURNS
J. CONCHIE
A. H. CONNEY
G. J. DUTTON
M. F. JAYLE
ROGER LESTER
G. A. LEVVY
C. A. MARSH
J. R. PASQUALINI
ROGER M. ROWELL
RUDI SCHMID
JEREMIAH E. SILBERT
R. L. SMITH
ROY L. WHISTLER
R. T. WILLIAMS
GLUCURONIC ACID
Free and Combined
CHEMISTRY, BIOCHEMISTRY,
PHARMACOLOGY, and MEDICINE
Edited by
GEOFFREY J. DUTTON
BIOCHEMISTRY DEPARTMENT
QUEEN'S COLLEGE
(UNIVERSITY OF ST. ANDREWS)
DUNDEE, SCOTLAND
ACADEMIC PRESS New York and London 1966
COPYRIGHT © 1966, BY ACADEMIC PRESS INC.
ALL RIGHTS RESERVED.
NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM,
BY PHOTOSTAT, MICROFILM, OR ANY OTHER MEANS, WITHOUT
WRITTEN PERMISSION FROM THE PUBLISHERS.
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United Kingdom Edition published by
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PRINTED IN THE UNITED STATES OF AMERICA
List of Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
J. J. BURNS, The Wellcome Research Laboratories, Burroughs Wellcome
and Company, Tuckahoe, New York (365)
J. CONCHIE, Rowett Research Institute, Bucksburn, Scotland (301)
A. H. CONNEY, The Wellcome Research Laboratories, Burroughs
Wellcome and Company, Tuckahoe, New York (365)
G. J. DUTTON, Biochemistry Department, Queen's College, University of
St. Andrews, Dundee, Scotland (185)
M. F. JAYLE, Laboratoire de Chimie Biologique, Faculté de Médecin,
Paris, France (507)
1
ROGER LESTER, Department of Medicine, University of Chicago,
Chicago, Illinois (493)
G. A. LEVVY, Rowett Research Institute, Bucksburn, Scotland (301)
2
C. A. MARSH, Rowett Research Institute, Bucksburn, Scotland (3)
J. R. PASQUALINI, Laboratoire de Chimie Biologique, Faculté de Médecin,
Paris, France (507)
3
ROGER M. ROWELL, Department of Biochemistry, Purdue University,
Lafayette, Indiana (137)
4
RUDI SCHMID, Department of Medicine, University of Chicago, Chicago,
Illinois (493)
1
Present address : Department of Medicine, Boston University School of Medicine,
2
Boston, Massachusetts.
Present address : Department of Biological Sciences, University of New South Wales,
3
Sydney, Australia.
Present address : Division of Wood Chemistry Research, Forest Products Laboratory,
4
Madison, Wisconsin.
Present address: Department of Medicine, University of California, San Francisco
Medical Center, San Francisco, California.
vi LIST OF CONTRIBUTORS
JEREMIAH E. SILBERT, Medical Service and Research Laboratory, Boston
Veterans Administration Hospital, and Department of Medicine,
Tufts University School of Medicine, Boston, Massachusetts (385)
R. L. SMITH, Department of Biochemistry, St. Mary's Hospital Medical
School, London, England (457)
ROY L. WHISTLER, Department of Biochemistry, Purdue University,
Lafayette, Indiana (137)
R. T. WILLIAMS, Department of Biochemistry, St. Mary's Hospital
Medical School, London, England (457)
Preface
Sixteen years ago Academic Press published " Biochemistry of Glucur­
onic Acid," a small volume of under a hundred pages. The object of the
authors, Drs. Artz and Osman, was to collect the scattered observations
of almost a century " as a service and possibly as a stimulus " to any future
investigators in that little-known field.
Since 1950, there has been so much new information on glucuronic
acid, free and combined, and such a great deal of speculation on its
physiological role that a similar appraisal would now seem necessary to
distinguish between fact, probability, and the many still unanswered
questions. Until this is done the direction of further advances will not be
clear.
Glucuronic acid is at present peculiarly suited for treatment in a single
volume. On the one hand, its rapid emergence into metabolic publicity
has brought many workers on its chemical, biochemical, pharma­
cological, and medical aspects into contact with each other and with their
unfamiliar disciplines ; on the other hand, the marked interrelation of their
findings has tended to become lost in the proliferation of specialist
journals.
This treatise seeks to unite, or at least to gather in one place at this
critical time, the important facts from all these fields and to indicate
which problems might be most rewardingly tackled. It may well become
as quickly out of date as its predecessor, but that would be an honorable
fate. The questions to be answered may be answered because they were
asked here.
This volume is arranged in three sections, dealing, respectively, with the
chemistry, the metabolism, and the "biological significance" of glucur­
onic acid. Because of recent advances, the first two sections can now be
treated reasonably fully; the third section must remain fragmentary. At
the present time we do not know why the organism should employ this
particular molecule in any metabolic step, and in a volume designed to
assemble facts, the pleasures of speculation are out of place.
In the first section, Chapter 1 details the chemistry of free glucuronic
acid and its simple derivatives, including glucuronides, and lists most
vii
viii PREFACE
of the known conjugates. Chapter 2 outlines the occurrence and chemistry
of the glucuronic acid incorporated in animal, plant, and bacterial
polysaccharides.
Introducing the metabolic section, Chapter 3 deals fairly fully with the
biosynthesis of glucuronic acid as UDPglucuronic acid and with its
linkage into simple glucuronides. Chapter 4 summarizes present know­
ledge of the enzymic hydrolysis of these conjugates and of the many
factors influencing release of glucuronate by this pathway. The sub­
sequent entry of glucuronic acid into general carbohydrate metabolism is
discussed in Chapter 5. Chapter 6 records work on the incorporation of
glucuronic acid into, and its release from, the polysaccharides of living
tissues and attempts to assess the metabolic significance of glucuronic
acid as a constituent of these molecules.
The value of glucuronic acid to the whole organism is further explored
in the third section in which three subjects are discussed. Each is of great
clinical interest, and each promises to help us understand how, and for
what reason, glucuronic acid is integrated with the bodily processes.
Chapter 7 discusses the pharmacological implications of the glucuronic
acid employed in drug detoxication ; Chapter 8 summarizes our recently
gained knowledge of the importance of glucuronate in bilirubin meta­
bolism ; and Chapter 9 deals with that slowly untangling problem, the
isolation, identification, and function of the steroid glucuronides.
Although emphasis is on D-glucopyranosyluronic acid, other less
well-known hexuronic acids are considered where relevant. When of
value, practical details of estimation, or references to them, are added as
appendixes to the chapters.
For brevity, certain accepted shorter terms are employed. Unless
otherwise indicated, they are as follows : "glucuronicacid" and "glucuro­
nate" for D-glucopyranosyluronic acid and D-glucopyranosyluronate,
respectively [the terms "D-glucopyranuronic acid" and "D-gluco-
pyranuronate," although less commonly used, might be preferable as
systematic names for the pyranose forms of the acid and the ion (see
Chapter 1, Section I)]. "Glucuronide " is used for a β-D-glucopyrano-
siduronic acid or for the jS-D-glucopyranosiduronate ion; in less strictly
chemical contexts there seems to be no advantage in using the longer and
no more precise " glucuronoside " or " glucuronidate " for these com­
pounds. "Uridine disphosphate glucuronic acid" ("UDPglucuronic
acid") is used for uridine 5'-pyrophosphate-D-glucopyranosiduronic
acid; although the shorter term "UDPglucuronate" has been employed
by the Commission on Enzymes of the International Union of Biochem­
istry (see reference 55, Chapter 3), it suggests, incorrectly, a linkage with
UDP through the C-6 atom of glucuronic acid. The systematic name for
PREFACE ix
th,is nucleotide given above may be less open to objection than uridine
5-(D-glucopyranosyluronic acid pyrophosphate), uridine 5'-(D-gluco-
pyranosiduronic acid pyrophosphate), or uridine 5'-(D-glucopyranurono-
syl pyrophosphate).
Purely as a convenience in certain contexts, the adjective "foreign" has
been used for a compound which has not itself, nor in any closely related
form, been found naturally in the species under discussion; otherwise
no differences between "foreign" and "endogenous" compounds are
implied.
It is a very great pleasure to acknowledge the help given to the editor by
the contributors to this volume and also by others engaged in glucuronic
acid research who freely made available their unpublished findings. To
list the names of everyone who helped is unfortunately not practicable;
but, apart from the contributors, special thanks are due to Drs. I. M.
Arias, B. B. Brodie, J. Dahl, A. K. Done, J. R. Fouts, V. Ginsburg,
N. D. Goldberg, J. K. Grant, T. Hargreaves, K. J. Hartiala, W. Z. Hassid,
K. J. Isselbacher, P. W. Kent, G. H. Lathe, T. A. Miettinen, A. M.
Nemeth, R. E. Park, D. A. R. Simmons, J. N. Smith, D. F. Tapley,
W. Taylor, R. S. Teague, and O. Touster. Particularly valuable help for
Chapters 1 and 3 was generously given by Drs. Ishidate, Okada,
Shioya, Tamura, and their colleagues in Japan. To his own colleagues in
Dundee, notably Drs. R. P. Cook and I. H. Stevenson, the editor also
extends his thanks for much useful discussion. Regrettably, Dr. L D. E.
Storey was not able to contribute a chapter or even part of one, but his
help and advice are gratefully acknowledged here. Needless to say, the
editor alone is responsible for the imperfections of the volume.
The courteous assistance of the publisher has been much appreciated.
August, 1966 GEOFFREY J. DUTTON
Introduction
GEOFFREY J. DUTTON
Although more detailed historical treatment will be found in the
relevant chapters, a short survey of the development of the study of
glucuronic acid and its present status may form a useful introduction.
A full list of references would be out of place here, and only a few of the
earlier ones can be mentioned.
The compound now known as glucuronic acid was first described as a
curious sugar acid occurring in the urine conjugated with certain drugs.
This led to it being christened "glykuronsaiire" by Schmiedeberg &
Meyer (/). The chemistry of the free acid and its lactone was usually
investigated on material obtained by hydrolysis of these biosynthetic
conjugates; there was no other convenient method of preparation.
Consequently, the chemistry and physiology of glucuronic acid were
linked from the start.
The limitations of such a biosynthetic source hampered chemical
studies, but did not prevent their progress. Crystalline glucuronolactone
was isolated by Schmiedeberg & Meyer in 1879 (7). Glucuronic acid itself
was synthesized by Fischer & Piloty in 1891 (2), but the procedure used
was difficult and the compound unstable, and not until 1925 was the free
acid isolated in crystalline form by Ehrlich & Rehorst (5). Further work
on its ring structure in naturally occurring polymers and conjugates and
as the lactone was carried out in the next 10 years by Challinor et al. (4),
Robertson & Waters (5), Pryde & Williams ((5), and Goebel (7), to name
a few of the most active workers in this field. Until the late 1940's,
however, our knowledge of the chemistry of this compound and its
derivatives was rudimentary because it was not obtainable in bulk and
was not considered of great physiological importance.
The role of glucuronic acid in the body was thought to be limited to the
conjugation of administered toxic compounds, and metabolic studies for
more than 50 years centered on, or circled around, the problem of the
origin of these urinary conjugates.
The wider occurrence of glucuronic acid, which was gradually being
revealed in the 1920's and early 1930's by analysis of mucins and of
bacterial and plant polysaccharides, was therefore somewhat overlooked.
XV
xvi INTRODUCTION
If considered at all, the function of glucuronate in these complex mole­
cules tended to be thought of as the provision of yet one more possible
source of glucuronate for urinary "detoxication" (8). However, several
workers at this time, especially Quick (9), were not satisfied that the only
role of glucuronic acid, even in simple conjugates, was a "detoxicatory"
one, and their views became general when in the mid-1930's work by
Marrian's group (70) and by Venning & Browne (77) revealed that
endogenous aglycons, such as phenolic steroids, were also excreted as
urinary glucuronides and presumably could also exist in the body as
glucuronides. This possibility of the wider physiological importance of
glucuronate was strengthened with the identification by Japanese
workers (72) of β-glucuronidase, an enzyme which could break down
these glucuronides in tissues. Further work by Fishman, Levvy, Mills,
and their colleagues in the 1940's resulted in much information on this
enzyme. Though technically very useful for hydrolyzing urinary con­
jugates, ^-glucuronidase had, despite invigorating controversy, no
obvious biosynthetic action and, at the time, disappointingly little
demonstrable significance in metabolism.
These studies swung attention away from the "foreign" conjugates
(on which, however, Williams continued his classical chemical and meta­
bolic studies) and, together with the increasing realization that glucuronic
acid was an important constituent of polysaccharides of potential clinical
interest such as heparin and hyaluronic acid, made extensive work with
the pure compound very desirable. There was a possibility, too, that
administration of large doses of glucuronate might assist the detoxication
of harmful "endogenous" or "foreign" substances. It was therefore
essential to find a simple method of preparing glucuronic acid or its
lactone in quantity.
Originally (2) the acid had been synthesized by reduction of glucaro-
lactone. Oxidative methods were simpler, and by the early 1950's large-
scale commercial synthesis based on the oxidation of starch or other
glucose-containing molecules had been achieved in the United States and
in Japan. To assist the work now made possible with cheap, plentiful
glucuronate, Artz & Osman (13) wrote a useful monograph collecting the
few scattered facts known then about the biochemistry of the compound.
At this critical period, biochemical techniques had advanced suffi­
ciently to use the newly available material with effect, and knowledge of
the metabolism of glucuronic acid at last progressed rapidly.
This progress was evident in three main fields. In the first, the bio­
synthesis of the simple conjugates of glucuronic acid was shown to occur,
somewhat ironically, not through the free glucuronate now available, but
by glucuronyl transference from an "active" form, uridine diphosphate