Speculations on the biochemical pharmacology of ethanol

Pergamon Press

Life Sciences Vol. 15, Pp. 617-633 Printed in the U.S.A.

MINIREVIEW SPECULATIONS ONTHEBIOCHPlICAL

PHARNACOLOCY OFETHANOL

Ralf G. Rahwan Division of Pharmacology, College of Pharmacy The Ohio State University Columbus, Ohio 43210

As early as the 1930's it was recognized that the primary metabolic product of ethanol, acetaldehyde, produced pressor responses in animals (1) that closely resembled the cardiovasculareffects of sympathomimeticamines. The pressor response to acetaldehyde is not blocked by ganglionic blocking aqents (2-5)s and is therefore not central in origin, and is reduced, but not abolished, by removal of the adrenal glands from the circulation (1,2,4,6). Such evidence suggests that acetaldehyde may be exerting a sympathomimetic action by liberating catecholaminesfrom peripheral storage sites (3,4,7). Acetaldehyde has in fact been shown to release catecholamines from the perfused adrenal gland (2,8-11). and to increase plasma norepinephrine (NE) levels when administered to cats and rabbits at a dose of 30 mg/kg body weight (12). Cohen & Collins (13) demonstrated that perfusion of isolated bovine adrenal glands with buffered acetaldehyde solutions resulted in the formation of tetrahydroisoquinoline(TIQ) derivatives, which are stable condensation products of the exogenous acetaldehyde and endogenous epinephrine (EPI) or NE. The reaction is a Pi&et-Spengler type of condensation (l&,15) between the aldehyde and amine with a resultant unstable Schiff's base intermediatewhich cyclizes to form the TIQ (Figure 1). These alkaloidal compounds (EPI-TIQ and NE-TIQ) can be formed on perfusion of adrenal glands with solutions containing 23 @? acetaldehyde (16), a concentrationwhich has been reported in the blood of man after ingestion of alcoholic beverages (16). 617

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CH3CH2’0H ethanol OH

HO

OH

1

CH3CHO acetaldehyde

HO

*

1

-

Ho

HO

CH3

dH3 Catecholamine

OH

Schiff's Base Intermediate

TIQ

FIGURE 1 The formation of tetrahydroisoquinolines from catecholamines.R31, norepinephrine and 1-methyllc,6,7-trihydroxy-i,2,3,4tetrahvdroisoauinoline(NE-TIQ). R=CH-. epinephrine and 1,2-dimethyl-&6,7-tr~~ hydroxy-1,2,3,&tetrahydroisoquinoline (EpI-TIQ).

Analogous condensation reactions occur with formaldehyde which reacts rapidly (13) with catecholaminesto form TIQs lacking a methyl group in the l-position. Evidence for adrenal TIQ synthesis -in vivo was obtained both by fluorescence histochemistry after administration of large amounts of nonradioactive methanol (17) and by thin-layer radiochromatographyafter administration of tracer doses of i&C-methanol (18). Similar condensation products between dopamine and acetaldehyde have been studied in rat brain and liver homogenates (19). Furthermore, administration of ethanol and 5-methoxytryptamine to rats in the presence of disulfiram (an aldehyde dehydrogenase inhibitor) and iproniasid (a monoamineoxidase inhibitor), resulted in the appearance in urine of 1,2,3,4-tetrahydro-p-carbolines, which are condensation products ofthealcohol-derived acetaldehyde with the indoles (20; -vide infra). It had been previously noticed that the TIQ alkaloids in acetaldehyde- or formaldehyde-perfusedhovine adrenals appeared to be bound in the adrenal tissue (13), and recently Greenberg & Cohen (8,21)

demonstrated that these

TIQs were indeed hound within the adrenal chromaffin granules (21), and were released together with the catecholaminesupon stimulation of the adrenal

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Speculations on Alcoholism

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medulla with acetylchollne or carbachol (8). Furthermore, information obtained in our laboratory (10) indicates that the catecholaminesand their TIQ derivatives can be differentiallyreleased from the adrenal medulla. The mechanisms of secretion from the adrenal medulla have been extensively studied by various laboratories including our own (10,22-24),and we have recently reviewed .thevalue of the adrenal medulla as a pharmacologicalmodel for the investigation of neuroendocrlnemechanisms (22). The pharmacologicaland toxicological profiles of the acetaldehyde-derived EPI-TIQ and NE-TIQ have not been investigated, primarily due to problems associated with their chemical synthesis. While most simple tetrahydroisoquinolines related to dopamine and to dopa are readily synthesized_in vitro by Pictet-Spengler condensation, the l-methylls-hydroxy-TIQsshown in Figure 1 have not been chemically synthesized in pure form (25-27). The major problem in the chemical synthesis of the 1-methyl-&hydroxy-TIQs appears to be in the purification and crystallizationof these compounds since diasterioisomersand dimeric addition products result (26).

It may, however, be feasible to devise

a biological source for obtaining sufficient quantities of these TIQs to initiate pharmacologicaland toxicological investigations.The bovine adrenal medulla would appear to be the most suitable biological model for quantitative biosynthesis of 1-methyla-hydroxy-TIQs due to its high content of EPI and NE, the ease with which it can be perfused with acetaldehgde, and the wealth of information already accumulated with this organ (22). and particularly since the synthesis (8,10,i3,16)and mechanism of release of these TIQs have already been elucidated with this organ (8,iO). Attempts in this direction are currently under way in our laboratory. The pharmacology of dopamine-TIQ (DA-TIQ, salsolinol), derived from the condensation of acetaldehyde and dopamine, is not known, though much speculation on its clinical significance has been presented. The structure of salsolinol is shown in Figure 2, along with the structures of salsoline and anhalamine, which are found in desert cacti (28).

and the saguaro alkaloid,

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gigantine,which causeshallucinogenic reactionsin squirrelmonkeysand in cats (29).Also shown in this figure is debrisoquine, a tetrahydroisoquinoline used clinicallyas an antihypertensive agent.A numberof othernaturally occuringplant alkaloidsproduceprofoundeffectson the centralnervousand cardiovascular systems(30-35).

::wH CH3 salsolinol

:t;:mH

C~;;mH CH3 salsoline

gigantine

OH anhalamine

debrlsoquine FIGURE 2

Chemicalstructuresof sdlsolinol and relatedtetrahydroisoqulnolines. It has been suggestedthat TIQs may form in man in adrenerglcneuronesas well as in the adrenalmedulladuringingestionof alcoholicbeverages(36), and that the TIQs may functionin viva as falsetransmitters(13,37).The criteriaidentifyinga compoundas a falseneurotransmitter (38) include demonstrating that it is storedat the same site as the physiological transmitter,and that it is releasedby the same stimuliwhich releasethe physiologicaltransmitter. Both of these criteriaare met by the acetaldehydederivedEPI-TIQand NE-TIQin model experimentsinvolvingthe adrenalmedulla (8). Recently,Heikkila-et al. (39) showed that TIQs can be takenup and accumulatedIn rat brain synaptosomes, and interferedwith the uptakeand releaseof catecholamines by the synaptosomes. TIQs are also takenup and accumulated In vitro by sympathetic neurons of the intactiris of the rat, a --

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process which can be blocked by desmethyllmipramine(40). Uptake -in viva of 6.7-dihydroxytetrahydroisoqlinoline into sympathetic nerves in mouse heart and subnaxillary glands and irides of rats has also been demonstrated (4-l), and could be blocked by chemical or surgical denervation or by inhlb?tors of catecholamineuptake (cocaine and desmethylimipramine). Since eplnephrine, norepinephrine,and dopamine constitute the major catecholamines in the body, it Is clear that their TIQ derivatives, if formed in vivo following alcohol consumption, would contribute to some pharmacological -responses to ethanol by interfering with catecholaminerglc(adrenergicand dopaminergic) mechanisms in the brain and in the periphery (8,36). This working hypothesis is supported by the recent finding that salsolinol can be recovered in significant quantities from the urine of patients with Parkinson's disease following alcohol consumption while under L-dopa therapy (42). Even in the absence of ethanol consumption, parkinsonian patients under L-dopa treatment show a relatively high output of urinary salsolinol (42). suggestive of an endogenous source of circulating acetaldehyde. There is evidence that ethanol is formed endogenously in rat, rabbit, and in man (43-

45). probably in the gastrointestinaltract (42). Whether EPI-TIQ and NE-TIQ are also formed -in vivo in the presence of exogenously administered or endogenously formed ethanol remains to be determined. It is very likely that a number of TIQs derlved from biogenic amines are spontaneously formed in vlvo, and contribute to physiologicaland pathological processes in the body (42). Sandler -et al. (42) recently presented evidente that tetrahydropapaverollne (a TIQ alkaloid formed by the condensation of dopamine with dopaldehyde derived from the oxidative deamination of dopamlne; Figure 3) can be identified in significant concentrationsin the urine of parkinsonian patients under L-dopa treatment, Tetrahydropapaverolinehas been shown to possess adrenergic beta receptor agonist activity (36).

Speculations

622

HO HO

Vol.

on Alcoholism

15, No.

4

Jo-

NH2

dopamine

dopaldehyde (3,4_dihydroxyphenylacetaldehyde)

tetrahydropapaveroline (N-norlaudanosoline)

FIGURE3 Possiblepathwayfor the biosynthesis of tetrahydropapaveroline. Normally,dopamine is metabolizedby monoamlneoridase (MAO) to 3,4-dihydroxyphenylacetaldehyde, and furtherconvertedto 3,4_dihydroxyphenylaceticacid by aldehydedehydrogenase. Becauseof the StNCtUId

similaritybetweentetrahydropapaveroline and

the morphinealkaloids(Figure4). Davis 8 Walsh (46) proposedthat the _in vivo formationof TI? alkaloidsmight form the biochemical basis of alcohol addiction.Independantly, but simultaneously, Cohen& Collins(13) advancedthe

tetrahydropapaveroline

morphine

FIGURE4 Chemicalrelationship betweentetrahydropapaveroline (N-norlaudanosoline) and morphine.N-norlaudanosoline is a known intermediate in the biosynthesis of mo in the opium poppy,Papaversomniferum

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same proposal. Briefly, this hypothesis proposes that the elevated brain levels of acetaldehyde following alcohol consumption would result in increased amounts of dopaldehyde (derived from the normal oxidative deaminatlon of dopamine) by saturating the enzyme aldehyde dehydrogenase which would normally oxidize dopsldehyde to 3,4_dlhydroxyphenylacetlcacid. With excessive dopaldehyde in the brain, condensation with dopamine can occur resulting in the formation of tetrahydropapaveroline(N-norlaudanosoline),which conceivably could undergo further biotransformationto morphine or morphine-like alkaloids by a sequence of reactions similar to those now known to occur in the opium poppy (Papaver somniferum). That tetrahydropapaverolinecan be formed -in viva in man has been established by Sandler e

a.(@).

The above hypothesis has been sharply criticized by Seevers (48) who pointed out that physical dependence and withdrawal from morphine and alcohol are quite dissimilar, and that cross-tolerancebetween these two addicting compounds does not occur, and neither does cross-dependenceas evidenced by the fact that morphine addicts prefer barbiturates, amphetamine, or cocaine over alcohol. In an Interesting rebuttal of Seevers' (48) criticisms,Davis & Walsh (49) pointed out that the dlfference in symptomatologybetween alcohol and morphine addiction and withdrawal does not militate against the concept that the same biochemical substrate may underlie the addiction with alcohol or morphine, and that the difference in symptomatologyand lack of cross-tolerance and cross-dependencebetween the two agents may be due to the fact that exogenously administered morphine may be acting diffusely throughout the brain whereas alcohol-inducedendogenously formed morphine-like alkaloids may be localized to those brain areas rich in dopamine (notably the infundibular and extrapyramidal regions) and which may be accessible to exogenously administered alcohol but not morphine. Sven if morphine were to reach the localized dopaminergic areas of the brain (which indeed it does at least in the caudate nucleus of the cat [501), the panorama of effects resulting from flooding the brain with morphine may mask any discrete alcohol-like symptoms. That narcotic

624

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antagonistsdo not precipitatealcoholwithdrawalmay again be relatedto the questionof accessibility of the discreteareas of the brain that may be involvedIn alcoholaddiction(49).Finally,althoughSeevers'(48) critique of the hypothesisof a commonbiochemicaldenominatorfor addictionto alcohol or morphineis basedvery heavilyon the symptomatological differencesbetween these two conditions, he offersno explanationfor the symptomatological discrepancybetweenthe responseof cats and dogs to morphineadministration despitethe qualitativesimilarityin brain distribution of morphinein both species(50). In an earliermodel of the etiologyof alcoholism, Martin (5l,52)proposed that the increasein acetaldehyde concentrations followingthe ingestionof alcoholwould resultin interaction betweenacetaldehyde and the sulfhydryl group of coenzymeA, thus preventingthe formationof acetylCoA and of acetylcholine.Reductionof acetylcholine in the brainwould then reducethe normal acetylationof sulfhydrylgroupson the histonerepressorsof the cholinergic receptorthat would otherwiseoccurduringhydrolysisof acetylcholine, and this fn turn would convertthe histonerepressorto neutralstatuswith a resultinginductionof receptorsynthesis.hartin'sgroup aid indeedpresent evidencethat alcoholingestionin rats reducedbrain CoASH activityand concentration (53) as well as the concentration of true chollnesterase (9). The latterobservationwas interpretedas a naturalresponseon the part of the body in an attemptto preservethe diminishedconcentration of acetylchollne inducedby alcohol(54).It was furthershownthat administration of cystelneto rats preventedthe alcoholinduceddrop in cholinesterase brain levels (54).and it was suggestedthat acetaldehyde would preferentially react with the sulfhdrylgroupsof cysteineinsteadof CoASH (54).

Flartin's group

interpretedsuch an inactivation of acetaldehyde as preventingthe biochemical sequenceof

events

leadingto cholinergic receptorInduction(54).

the latter

phenomenonbeing presumablyresponsiblefor renderingthe individual"hyper-

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Speculations on Alcoholism

625

sensitiveto his environment"(withdrawal ?> shouldhe stop drinking(53). Martin'sgroup,however,never demonstrated any directevidencefor their originalconceptof receptorinduction , aa

if one were to consideracetyl-

cholinesterase as a receptorfor acetylcholine then theirdata (54) on alcohol inducedalterationin brain cholinesterase levelswould indicatea reduction ratherthan an inductionof receptors. AlthoughMartin's(51.52)model for alcoholaddictionsummarizedabove involvesa chollnergic mechanism,acetaldehyde plays the pivotalrole in the biochemicalsequenceof reactionsproposed.It Is thereforeentirelyconsistent with this centralrole of acetaldehyde that TIQs, ratherthan cholinergic receptors,may be the basis for alcoholaddiction.The demonstration of tetrahydropapaveroline in humans (42) (videsupra)lends credenceto the increasingly populartheoryfor a role of TIC& in alcoholaddiction.Furthermore, the projectionby Martin'sgroup (54) that physicaldependenceon alcohol can be preventedby cysteineis again consistentwith recentfindingson TIQ biosynthesis. Thus, the in vitro condensation of dopaldehyde with dopaminein rat brain homogenatesto form tetrahydropapaveroline Is preventedby cysteine (55).

In viva, cysteineprotectsrats againstthe toxicityand lethalityof

acetaldehyde(56).

and reducesalcoholapetitein the same species(H. Sprince,

quoted in 55). Since inhibitionof TIQ formation_in vivo by cysteinehas not yet been demonstrated, the significance of thesefindingsIn relationto the behavioraleffectsof alcoholremainspeculative(10). Variousotheragentsare known to Interferewith TIQ biosynthesis In vitro. _Thus, In additionto cysteine , ascorbateand glutathlonepreventthe formation * of tetrahydropapaveroline from dopamlneand dopaldehydein rat brain homogenates (55).

Presumably,the mechanismof Inhibitionis differentwith each

agent.Thus, ascorbateand glutathioneact eitheras reducingor complexing agents,while cysteinetends to fonn thiazolidine derivativeswith aldehydes (55).

Recently,thyrotropln-releasing-hormone was found to antagoniseethanol

narcosisand hypothermiain mice (57)by an as yet undetermined mechanism.

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Speculations on Alcoholism

Davis & Walsh (49)

Vol. 15, No. 4

pointed out the areas of research that should be

embarked on in order to validate a role of TIQs, if any, in alcoholism. Thus, it remains to be determined whether tetrahydropapaveroline,fonned -in vivo followlng alcohol ingestion, is localized within dopaminergic neurons In specific brain areas; whether tetrahydropapaverolinecan undergo metabolic transformation to morphine or morphine-like alkaloids similar to that occuring in plants: whether endogenously fonned morphine-like alkaloids have any relevance to alcoholism: and whether narcotic antagonists administered into the dopaminergic areas of the brain would antagonlse alcohol addiction.

The possible pathological role of TIQs is not limited to alcoholism and parklnsonlsm (vide m).

Thus, Sourkes (58) drew attention to the similarity

in structure between the tetrahydxopapaverolinemolecule and apomorphine and bulbocapnine (Figure5). The lattercompoundwill producea catatonia-like

state in animalsreminiscentof one manifestation of schizophrenia. Since L-dam tends to bring about a deterioration In schizophrenic subjects,It has been proposed(42) that the structurally relatedtetrahydropapaveroline, formedfrom L-dopa (videsupr~),may be responsiblefor this deterioration. However,if one were to assumethat tetrahydropapaverollne formationis at least in part responsiblefor the symptomsof parkinsonism (42) as discussed earlier,then any conclusionsregardingstructure-activity relationships betweentetrahydropapaveroline and bulbocapnine or apomorphine must be guarded sinceboth lattercompoundshave been shownto have antitremoractivityand were at one time or anothersuccessfully tried in parkinsonism, thoughtheir clinicaluse is obviouslyrestrictedby their toxicity(59).

Despitethis

dlsparlty,Sandlere al. (42) pointout the possibilitythat endogenous formationof tetrahydropapaverollne may underliethe biochemical basis of schizophrenia. The ldentiflcatlon of tetrahydropapaverolinein the parkinsonian Individual(42) and the recognition of its adrenerglcbeta receptoragonist activity(36).

capled with the known clinicalefficacyof the adrenergicbeta

Speculations on Alcoholism

Vol. 15, No. 4

receptorantagonist,

propranolol,

presents

stronger

627

evidencefor a role of

this TIQ in parklnsonism than the circumstantial evidencefor any involvement in schizophrenia.

tetrahydropapaveroline

apomorphlne

bulbocapnine

Structural relationship between tetrahydropapaveroline, apomorphine, and bulbocapnine. Sandler -et al. phenylketonuria agent,

phenylpyruvlc

by virtue

phenylketonurla

suggested

may originate

normal individuals, tyroslne

(42)

acid,

that the mental disorders

from the disproportionate

almost all

of phenylalanlne

of the action

the metabolism

of phenylalanlne

and phenylacetic

acid

(60).

acid,

with

of a carbonyl amines. In

metabolism is channeled through

of phenylalanine

hydroxylase. is diverted

F’henylpynwic

amounts as great as 1 to 2 grams per day in this to phenyllactic

presence

which may form a complex with biogenic

phenylpyruvic acid by transamination.

metabolized

associated

However, in to formationof

acid may be excretedin

condition,

o-hydroxyphenylacetlc

acid,

or may be further benzoic

acid,

The carbonylcompoundscould then conceivably be

metabolizedto the respectivealdehydeswhichwould condensewith endogenous biogeniceminesto form TIQ derivatives

(Figure

6).

It should be emphasized,

however,that confirmation of this aberrantmetabolicpathwaycan come only from the demonstration of TIC&sin body fluidsof phenylketonuria patients. The gas chromatographic methodused by Sandler9 &.

(42) to detectsalsolinol

and tetrahydropapaverollne in the urine of parkinsonian patientscould probably detectsmallamountsof TIQs in the urine of patientswith phenylketonurla.

628

Speculations

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Vol. 15, No. 4

CH2-FH-COOH NH2 L-phenylalanfne transamination

CH2COOH

CH2-CH-COOH

QJ

bH

phenylacetate

phenyllactate

CH2-YH-CHO OH phenylacetaldehyde

2-hydroxy-3-phenylpropionaldehyae

OH HO

HO

OH HO

HO

HO

HO $H-CH2 OH

tetrahydroisoquinoline

tetrahydroisoqulnollne FIGURE6

Hypothetical biosynthetic pathway of the tetrahydrolsoquinolines in phenylketonuria. Condensation between the aberrant carbonyl metabolites and end enous norepinephrine (NE) or domine (DA “5 would conceivably result in foxmatlon of complex tetrahydroisoqulnollne alkaloids.

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Speculations on Alcoholism

As earlyas 1961,McIsaac(61) proposeda generalbiochemicalconceptof of endogenously formedaldehydes mentaldisease,involvingthe condensation to form the hallucinogenic with the serotoninmetabolite,$methoxytryptamine, IO-methoxyhannalan (Figure7),

a potent serotonin

antagonistand MAO inhibitor.

The latteractionwould inhibitoxldativedeamlnationof serotoninand shunt with a resultingself-perpetuating generation its metabolismto 0-methylation, of lo-methoxyhannalan.

I-methyl-6-hydroxy1,2,3,4-tetrahydro-fi-carbollne

oxidative deamination

+methoxytryptamine

l-methyl-6-methoxyN-oxide derivative 1,2,3,4-tetrahydro+?-carboline

N-acetyl-5-methoxytryptamine lo-methoxyhannalan FIGURE7 Biosynthetic pathwayof tetrahydro-!carbolinesand lo-methoxyharmalan. The &shed arrowsindicatehypothetical dehydration reactions.Monoamineoxidase (MAO)and hydroxyindole-kaethyltransferase(HIOMT)are normallyinvolvedin the metabolictransformation of serotonin. That alcoholmay participatein the biosynthesis of thesefi-carbollnes was demonstrated both _in vitro and -in vlvo by Dajanl& Saheb (62).

Thus, adminlst-

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Speculations on Alcoholism

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ration of ethanoland 5-hydroxytryptophan (serotoninprecursor)to rats under

appropriateconditions(pretreated with pargyllneand disulfiramto inhibit respectively) resultedin the formationof MAO and aldehydedehydrogenase, l-methyl-6-hydroxy-l,2,3,4-tetrahydro-~-carboline and I-methyl-6-methoxy1,2,3&t-tetrahydro-fi-carboline (Figure7). which couldbe recoveredfrom the urine of the animals.Furthermore, incubationof brain homogenates with acetaldehydeand serotoninunder appropriateexperimental conditions, resultedin the formationof the two aforementioned compoundsIn additionto the N-oxide derivativeof l-methyl-6-methoxy-l,2,3,4-tetrahydro-~-carboline and lO-methoxyhannalan.Dajani& Saheb (62) suggestedthat some of theseB-carbollnes may participatein the developmentof alcoholdependenceand in other pharmacologicaleffectsof ethanol. Althoughpursuitof the biochemicalapproachto alcoholismmay not appeal to many criticsof basic research,yet some of the most tangibleclinical benefitsdid indeedemergefrom such endeavorsas evidenced,for example,by the recentrecognitionof the role of the estrogenreceptorin the hormonedependentor autonomousmammarycarcinomas(63). Acknowledgment Supportedby NIMR Grant 1 R03 AAOll99-01from the U.S. Departmentof Health,Education,and Welfare. References 1. H. HANDOVSKI,C. R. SeancesSot. Biol. Filiales117, 238 (1934). 2. J. AKABANE,S. NAKANISHI,H. KOHEI,R. MATSUMURA,and H. OCATA,Jap. J. F'hannacol. &, 295 (1964). Exp. Ther.z, 3. N. R. EADE, J. F'harmacol.

29 (1959).

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