Ciba Foundation Symposium - Enzymes and Drug Action

576 Pages·1962·23.044 MB·English

ENZYMES AND
DRUG ACTION
Cibe Foundation Symposia
General Volumes
MammalianGermCells - - - - -
Preservation and Transplantation of N o d
Tissues - - - - - - -
LeukaemiaResearch - - - - -
Chemistry and Biology of Pteridines -
Porphyrin Biosynthesis and Metabolism -
Histake - - - - - -
Extrasensory Perception - - -- -
Bone Structure and Metabolism - -
Ionizing and Cell Metabolism -
Radiations
TheNatureofViruses - - - -
Chemistry and Biology of Purines - -
Drug Resistance in Micro-organisms - -
TheCerebrospinalFluid - - - -
Amino Acids and Peptides with Antimetabolic
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Medical Biology and Etruscan Origins - -
Biosynthesis of Terpenes and Sterols - - -
Carcinogenesis: Mechanisms of Action - -
Biochemistry of Human Genetics - - -
Significant Trends in Medical Research - -
CongenitalMalformations - - - -
Haemopoiesis: Cell Production and its Regula-
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AdrenergicMechanisms - - - - -
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A leajet giving details of the Ciba Foundafion Colloquia on
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CIBA FOUNDATION SYMPOSIUM
Jointly with
CO-ORDINATING COMMITTEE
FOR SYMPOSIA ON DRUG ACTION
on
ENZYMES AND
DRUG ACTION
Eriitorfor thc Co-ordinating Committec
J. L. MONGAR, PH.D.
Editorfor the Ciba Foundation
A. V. S. de REUCK, M.SC., D.I.C.
With 90 Illustrations
LITTLE, BROWN COMPANY
AND
BOSTON
1962
LIBRARY OF CONGRESCSA TALOCGA RD
NUMBBR:
61-16595
ALL RIGHTS~ E R V B U
This book is protected under the Benie Conuedon.
It may not be reproduced by any means, in whole
or in part, without permission. Application with
regard to reproduction should be addressed to tht
Publishers.
Printed in Great Britcritt
PREFACE
THISs ymposium is the eighth in the series organized by the
Co-ordmating Committee for Symposia on Drug Action. In
choosing so general a subject as Enzymes and Drug Action it was
hoped to take account of some of the many growing points in
biochemistry which are likely to be of importance for future
advances in pharmacology.
The symposium was divided into two parts. The first took
the form of a meeting at the Wellcome Building with papers and
discussion before an audience of about three hundred. The second
took the form of a small meeting at the Ciba Foundation consisting
almost entirely of unscripted discussion by a panel of about
thirty participants. The proceedings at these two meetings are
published in separate sections of the present volume as one of
the series of Ciba Foundation Symposia. It is edited jointly by
the Co-ordinating Committee for Symposia on Drug Action and
by the Ciba Foundation.
The main responsibility for the meeting lay in the hands of
the British Pharmacological Society with the co-operation of the
Biochemical Society, the Physiological Society and the Royal
Society of Medicine. The Organizing Committee consisted of
W. A. Bain, F. Bergel (Chairman), A. C. Dornhorst, H. McIlwain,
J. L. Mongar (Secretary) and H. 0. Schild. The Committee is
grateful to the Wellcome Foundation for the facilities provided
at the Wellcome Building, to the Wellcome Trust for financing
the Symposium, and to the Ciba Foundation not only for generous
hospitality and travelhg expenses for some of the overseas
members, and for providing a unique Conference Room whose
intimate atmosphere provided an ideal setting for the second
part of the meeting, but also for the excellent editorial fadties
which make possible the early appearance of the proceedings of
the symposium.
"
CONTENTS
Wellcome Building Sessions
Sessioii 1 :E nzymes as Primary Points o f Drug Action
Chairman: F. BERCEL
PAGE
Chairman’s introduction . . .
I
Inhibition acetylcholinesterase
of
by I. B. WILSON . . . 4
Discussion: ALDRIDGEB, ECKEITB, ERGELB,L ASCHKKOR, EBS,R . J. P.
WILLIAMS, WILSON . . . . 13
Carbonic anhydrase inhibition and physiological
by H. W. DAVENPORT. . . fu nction 16
Discussion: BBRGEL, BLAIR, DAVENPOHRUT,N TL, UTWAK-MANN, J. P.
Wn.Lims . . . R.. . 37
Session 2: Active Transport
Chairman: W. WILBRANDT
Pinocytosis
by H. HOLTER . 30
Discussion: GOLBERGH, OLTERSO, LS,Y OUNG . 39
Possible mechanisms active transport
by W. WILBRAofN D. T . . . . . 43
Discussion: HOLTERSM, YTH, WIDDAS, WILBHANVT . 57
Effects drugs active transport
byo fK . H. BBonY ERan d J. E. BAER. . 60
Discussion: BEYERW, ILBRANDT . . . 82
Session 3: Multiple Mechanisms
Chairman: J. H. GADDUM
I. Insuliri
The explanation the action insulin sugar permeability at
of of on
molecular level
by R. B. FISHER . . 83
on metabolic reactions
Actionb yo fE .in Bsu.l iCnH AIN . . . 9s
Discussion: BUSH, CHAIN, DANIELLdIe, DUVE,F ISH~R,K EYNES,
MARRACKSO, LS, WILBRANDT, WQLLENBBRGEB, YOUNG . . I I0
vii
viii CONTENTS
PACE
11. Digitalis
Acdon of cardiac glycosides ionic movements
byM.WmmmtN.L .o n . . . .
Digitalis: action metabolism and the contractile system
by A. WOLoLnE NBERGBR . . . .
127
Discussion: BAKERD, RAPERE, DMAN, KEYNES,W ASER, WHI'ITAM,
WOU~NBERGER. . . . . 150
111. Central Nervous System Depressants
Action of barbiturates upon respiratory enzymes
by W. N. ALDXUDCE. . . . . . 155
Appraising enzymic actions of central depressants by examining
cerebral tissues
by H. MCILWAIN . . . . . . .
170
Discussion: ALDRIDGEB, RADLEYC,R EMERD,R APERJO, HNSONJU, DAH,
KXYNES, MCILWAIN, NICOLLS,P HILLIS, W m m ,
REMMER,
R. J. WILLIAM. S . . . . .
P. I99
Session 4: Receptors
Chairman: W. D. M. PATON
Relation between enzymes and cholinergic receptors
by P. G. WASER . . . . 206
Discussion: Corm, CREESBH, OBBIGEWR,A SER . .
218
Induction of receptors
by R. MILIDI . . . . . 220
Discussion: BECKETTD,O RNIIORST, PATON, PETERSV, RBOVA,
ZAIMls . . . M.ILB. DI , .
236
Session 5: Altered Drug Metabolisni
Chairman: T. WILLIAMS
K.
Chairman's introduction . . . . * 239
Adaptive enzymes in animals
by W. E. KNOX . .
* 24s
Discussion: BERGBL, . . .
FISHER, KNOX 274
tolerance
Drug byH.RHMMBR . . . . .
Discussion: Re~~aSnC,H ULMARN., T. WILLIAMS. . . 227968
CONTENTS ix
PAGE
The genetics of drug sensitivity with special reference to suxa-
methonium
by H. HARRIaSn d MARYW HITTAKER . . 301
Discussion: AMBACHEB. LASCHKDOA, NIE~JH, ARRISH,O BBIGEKRN, OX,
.
h4ILED1, SPINKS 313
Session 6: Drug Metabolism: Subcellular Aspects
Chairman: SIR RUDOLPPHL TERS
Drug metabolism-subcellular mechanisms
by B. B. BRODIE . . ’ * 3x7
Discussion: BECKEWB, RODIEL, ACEYN, IMMO-SMITHK, BMMBRR., J. P.
WILLIAMS . 340
’
Cellular injury by drugs
by K. R. REES . . 344
Protection against cellular injury by drugs
by J. D. JUDAH . . . . 359
Discussion: ATKINSONB,R ODIED, RAPERG, OLBERCJU, DAH.O ’BREN,
PATONR, EES, REMMERW, EATHERAL. L . 384
Session 7: lhwl Discussion
Chairman: J. F. DANIELLI
Speakers: ALDNDGEB, ERGELB, LASCHKOB, RODIE,d c DUVE, FISHER,
GADDUMH,O LTERJU, DAHM, CILWAINP, ATONP. BTERSR, EMMERSH, UL-
SMYTHS,O LSS, PINKSW, ASERW, EATHERAWLLIL, RRANDRT. J, . P.
MWANIL, LIAMRS., T. WILLIAMS. . 386
Ciba Foundation Sessions on Drug-Enzyme
Interaction at the Molecular Level
Chairman: SIR HANSK REBS
Session 1: Etizymes
Introduction: Enzymes
byJ. F. DANIELLI . . 401
Models of active centres: acetylcholine . . . 410
Advetransport . . .
418
X CONTENTS
PAGE
Mode of action of . . . . . . . .
insulin 423
. . . . . 429
Limitationsofenzymesasmodels
Speakers: BELOFF-CHAIN, BERGELB, RODIB, DALE,D ANLELLI,
CHAIN,
de DWE, GADDUMH, OLTERb, s , M CILWAIN,
FISHER, SCHILD,
WASERW, ILBRANDRT., J. P. WILLIAMSW, ILSON
Session 2: Receptors
Introduction: Receptors
by H. 0. SCHILD . . . . . 435
Definition of receptors . . . . . . 439
Identifying active cenhes . . . . . 443
EiFect of denervation on receptors . . . . . 451
Events at the cell membrane . . . . . . . 453
Rate theory of drug action . . . . 456
Speakers: BERGELB, EYERB, RODIEC, HAIN,D ALE,D ANIELLId, e DWE,
FISHER, GADDUMJU, DAH, KATZ, KREBS, MCILWAIN, h’biDI, PATON,
PETERS, WASERR, . J. P. WILLIAMS,W ILSON,W OLLBNBBRGBR
SCHILD,
Interaction at the Subcellular and Cellular Levels
SIR RUDOLPHPE TERS
Chairman:
Session 3: Subcellular Level
Introduction: Membranes
by C. DE DWE . . 463
Subcellularparticles . . . 472
Phosphatidic acid cycle . . . . . 478
Antihistamines and membrane permeability . . . 481
Drug concentrations in vitro . . . 484
Speakers: ALDmce, BLASCHKBOR. ODIED,A NIELLDIA, VENPORdTe ,D UVE,
GADDUMH, OLTERJ,U DAH, KREBS, MChWNN, PETERS, hES, SCHILD,
WEATHERALL,W HI-ITAKEWRI, LBRANDT
Session 4: Cellular Level
Introduction: Cellular aspects
by H. MCILWAIN . . . 487
Reconstituting in vitro . . . 488
In vitro and in vivo . . . . . . . * . 494
CONTENTS xi
PAGE
Miaosomalenzymes . . . . . 497
Endoplasmicreticulum . . . 505
Enzymes young animals . . 50s
in
TransamiaaseandGABA . . 514
Druginteractions . . . . . . . 516
General considerations . . 518
Speakers: ALDRIDGBEE, RGEL, BLASCHKBOR, ODIEC, HAIN,D ALE,
BEYER,
DAVENPORDTO, RNHORSdTe , Dm, GADDUM,
FISHER, HARRIS,
HOLTFRJ, UDAH, KNOX. Mchwm, PJXERS, REMMER, Scm,
WHlrrAKER, R. T. WILLIAMS, WOLLENB6RCER