Analysis and the effects of some drugs on the metabolism of phenylethylamine and phenylacetic acid

Prog. Neuro-Psychopharmocol. Printed in Great Britain.

All

ANALYSIS

& Biol. Psych&. rights reserved

1964,

Vol.

6, pp.

607-614 Copyright

0

027&5846!64 $0.00 + SO 1964 Pergamon Press Ltd.

AND THE EFFECTS OF SOME DRUGS ON THE METABOLISM PHENYLETHYLAMINE AND PHENYLACETIC ACID PAUL S. Douglas

Hospital

Research

OF

MCQUADE

Centre,

Verdun,

Quebec,

Canada

(Final form, July 1984)

Contents

1. 2. 2.1. 2.2. 2.3. 2.4. z. 4:1. 4.2. 2: ;:

Abstract Introduction Assessment of PE Concentrations Radi oenzymat i c Method Gas Chromatograph i c Methods High Resol ut ion Mass Spect romet ry Gas Chromatography-Mass Spect romet PE Concentrations in Brain Tissue Phenylacetic Acid Gas Chromatography Gas Chromatography-Mass Spect romet Phenylacetic Acid Concentrations Drug Effects Effects on Other Neurotransmi tters

607 608 608 608 608 608 608 610 610 610

ry

ry

and

610 610 611 611

Neuromodulators

Conclusions

612 612

References

Abstract McQuade, Paul S.: Analysis amine and Phenylacetic Acid. 607-614. I. 2.

3. 4.

and the Prog.

Effects of Some Drugs Neuro-Psychopharmacol.

on the Metabolism & Biol. Psychiat.

of

Phenylethyl-

1984, 2 (4-6):

Phenylethylamine has been reliably measured using radioenzymatic, gas chromatographic, mass spectromatic and gas chromatographic - mass spectrometric methods. Phenylacetic acid has been measured using gas chromatographic and gas chromatographicmass spect romet ri c methods. Phenylethylamine concentrations are increased primarily by phenylalanine, its amino precursor and by such monoamine oxidase inhibitors as L-deprenyl and pargyline. Phenylethylamine administration influences other neurotransmitters such as dopamine, norepinephrine and 5-hydroxytryptamine. It also effects the tyramines and possibly t ryptami ne.

Keywords : spectrometry,

phenylethylamine, high resolution

phenylacetic acid, mass spectrometry,

gas chromatography, neuromodulator,

gas chromatography-mass dopamine, tyramines.

Abbreviations: cerebrospinal fluid (CSF), di (2-ethylhexyl) phosphate (DEHPA), dopamine (DA), gamma-aminobutyric acid (GABA), gas chromatography (GC), gas chromatography-mass spectromet ry (GC-MS) , 5-hydroxyt ryptamine (5-HT) , mass to charge ratio (m/e) , norepinephri (NE), pentafluoropropionyl ester (PFP), support coated open tubular (SCOT).

607

acid

ne

608

P. S. McQuade

1.

Introduction

The administration animal’s premature

of B-phenylethylamine to rats produced behavioral changes such as the awakening from anaesthesis and an increase in spontaneous motor activity in 1947, first proposed that the behavioral Holtz, Credner and Heepe, (Al les, 1933). effects produced by PE administration were very similar to those produced by amphetamine thus giving rise to the view that PE represents an “endogenous amphetamine”. PE is rapidly metabolized to form phenylacetic acid by monoamine oxidase isoenzyme B (Curtius et al., 1972; Yang and Neff, 1973; Durden and Phillips, 1980). With the observation of Potkin et al (1979) that PE may be excreted in elevated amounts by paranoid schizophrenic patients and by some bipolar affective patients (Fischer et al., 1972; Karoum et al., 1982) and the subsequent reports that PAA may be reduced in these patient populations of accurately measuring both PE and its major (Karoum et al., 1984) as we1 1, the importance metabolite, PAA, becomes apparent.

2. PE has 2.1.

been

assessed

Radioenzymat

in

Assessment

brain

tissue

of using

PE Concentrations the

following

methods.

i c Method

In 1974, Saavedra published a radioenzymatic method for PE estimation wherein the PE was first converted to phenylethanolamine using a dopamine beta-hydroxylase preparation and by using phenylethanolamine-N-methyl transferase to add a tritiated methyl group to the phenylProblems with this assay may arise from impure enzyme preparations which may ethanolamine. contain both other enzymes and other amines and also from the heavy reliance on the enzymesubstrate speci f i ci ty. 2.2.

Gas Chromatographi

c Methods

Edwards and Blau (1973) used electron capture detection to measure PE in the brains of Control PE concentrations rats which had been pretreated with pargyline and phenylalanine. were quite large (60 ng/gm wet weight) possibly a result of the use of packed columns to The use of DEHPA, a liquid cation exchanger, was a novel feaisolate the derivatized PE. ture of the procedure used to purify PE when it is present in large amounts (Martin and PE was then analyzed as a pentafluoropropionyl derivative by electron capture Baker, 1976). it was fi rst necessary to acetylate PE To measure lower concentrations of PE, however, GC. using acetic anhydride and subsequently react this derivative with pentafluoropropionic anhydride to form the N-acetyl-N-pentafluoropropionyl derivative, a compound having good Most recently, Hampson et al (1984) electron-capturing properties (Martin and Baker, 1977). diester of have used DEHPA to extract PE from rat brain. The N-acetyl , N-pentafluorobenzyl The regional disPE yields a very good positive chemical ionization fragment at m/e - 316. presented in Table 2, was determined by Reynolds et al tribution of PE in the ovine brain, GC techniques while very sensitive are not (1980) using the pentafluorobenzyl ester of PE. Extenvery selective thus one must purify the tissue samples extensively before analysis. sive 2.3.

purification High

can

Resolution

thus

reduce

the

Mass

Spectrometry

actual

tissue

sensitivity.

The high resolution mass spectrometry technique employs three individual thin layer chromatographic steps to isolate the dansyl (5-dimethylamino-I-naphthalene sulfonyl chloride) PE. The fragments - m/e 354.1402 (from the endogenous PE) and m/e - 356.1527 (from the deuterated standard) were measured by solid probe electron impact high resolution while very sensitive and specific, This technique, mass spectrometry (Durden et al ., 1973). involves considerable sample preparation and very expensive equipment. 2.4.

Gas

Chromatography-Mass

Spectrometry

Willner et al (1974) used solvent extraction to isolate the tissue PE and derivatized the The PFP-amine was fragmented by electron imextract with pentafluoropropionic anhydride. Karoum et al pact and the ratio of the m/e fragments 104 and 91 was used to identify PE. (1979) used Wilner’s procedure as a basis to measure a number of trace amines in various The major criticism addressed to this GC-MS technique is that the choice of tissues.

Effect

derivative potential much

higher

is

poor

as

the

m/e

contamination. in

the

of

on phenylethylamine

fragments

Thus brain

drugs

in

regions

are

Table they

of

2,

too

Karoum

low

a mass

et al Suzuki

examined.

metabolism

to

609

lessen

(1979) found and Hattori

the

possibility

PE concentration (1983) changed

of to

be

the

derivative employed to assess the final PE concentrations in rat brain. They used carbon disulphide to form the very stable isothiocyanate derivative of PE which fragments in the electron impact mode to form the molecular ion at m/e - 163. Edwards et al (1979) used positive chemical ionization GC-MS, a different method of fragmentation, after derivatizing PE with 2,4_dinitrobenzene sulfonic acid to form dinitrophenyl-PE. This compound reacted Similarly, Beckman et al with methane to give a positively charged fragment of m/e - 288. (1982) used positive chemical ionization with methane as the reactant gas to produce fragments of m/e - 318 (nondeuterated PE) and 327 (deuterated PE) for quantitation of the heptaThey initially isolated PE by fluorobutyryl ester of PE in human cerebrospinal fluid (CSF). In conclusion, one should using a Cl8 Sep Pak cartridge and 70% methanol to elute the PE. consider the GC-MS methodology as currently holding the most promise for future development.

Table Concentrations

of

phenylethylamine

(rig/g Human Human Rat

(Whole (Whole (Whole

I in

Brain) Brain) Brain)

Martin Willner Edwards Karoum Suzuki Fischer nourish

b:: 549; I.5

Table Distribution

of

phenylethylamine

Region Ovi nea

1.9

Caudate Nucleus Putamen Hypothalamus Medulla Cerebellum Hi ppocampus Cortex Pon s Substantia aReynolds bDurden

Nigra et

and

al

2 in

various

areas

Species Ratb Rate (ng/gm wet weight)

of

30.7 54.5 -

5.2 7.7 2.4-7.7

I.1

2.1

6.8

I.0 1.8 I.3

I.3 -

47’: 618 -

9.4 3.6 6.6 -

‘Karoum dPhilips

et et

the

Humand

4.2 2.1 1.6

(1982)

species

and Baker (IV761 et al (1974) et al (1979) et al (1979) and Yagi (1976) et al (1972) et al (1982)

2.3 I.3 1.6

(1980)

Boulton

various

Phillips et al (1978) Mosnaim and lnwang (1973) Durden et al (1973) Saavedra (1974) Suzuki and Hattori (1983)

I.5 I 80 I.8

Brain)

of

Reference

I.7

(Whole

brains

Amount wet wt.)

I.5 1.4 I.1

Mouse

the

al al

(1979) (1978)

brain

P. S. McQuade

610

3.

PE Concentrations

in

Brain

Tissue

PE has concentrations in the rat whole brain of from 1 to 2 ng/gm of Human and mouse brain have similar concentrations. Those concentrations Mosnaim and lnwang (1973) and Fischer et al (1972) were much too large nonspecific photometric method, The concentration published by Suzuki obtained with a modified spectrophotometric procedure was much lower.

wet tissue (Table suggested by due to the use of and Yagi (1976)

1). a

From Table 2, it is apparent that PE is found in highest concentration in the caudateputamen of both the rat and ovine brain. In human brain, the cerebellum contains the greatest concentrations of PE while the cortex, caudate-putamen and hypothalamus also contain substantial amounts.

4. PAA concentrations 4.1.

Gas

in

various

fluids

Phenylacetic and

tissue

Acid have

not

yet

been

extensively

investigated.

Chromatography

Goodwin , Ruthven and Sandler (1975) first measured phenylacetic acid in human urine by using flame ionization detection of the n-propyl-derivative of PAA. GC separation was performed on a SE-30 support coated open tubular (SCOT) capillary column. In order to reduce the volatility of the PAA, the PAA was first reacted with triethylamine to form a less volatile salt. Flame ionization detection of phenylacetic acid after derivatization with bis (trimethylsilyl) trifluoroacetamide also allowed Gusovsky et al (1984) to measure total phenylacetic acid excretion in man. Davis and Boulton (1981) measured phenylacetic acid in the urine by gas chromatography employing electron capture detection. The derivatization was achieved with pentafluorobenzyl bromide reacted in the presence of a catalyst, 18-crown-6ether. 4.2.

Gas

Chromatography-Mass

Spectromet

ry

Phenylacetic acid concentrations were measured in plasma and CSF after extraction with ethyl acetate, converted to the triethylamine salt and reacted with ethanolic potassium hydroxide containg 2% pentafluorobenzyl bromide. The molecular ion, m/e - 316 for the endogenous PAA, was monitored after electron impact fragmentation (Fellows et al., 1978). Martin et al (1979) also assessed PAA in the urine using the pentafluoropropyl derivative which after electron impact fragmentation produced a molecular ion of m/e - 268. Concent rations of PAA in the rat brain were assessed by Durden and Boulton (1982). The trifluoroethyl derivative was used. The derivatized acid was separated upon a SP-2250 50 meter SCOT column and under electron impact in the high resolution mass spectrometer yielded molecular ions of m/e - 218.0555. The concentration of PAA in both rat and mouse brain is from 20 to 30 fold higher than the PE concentrations. Highest concentrations of both PE and PAA are found in the caudate and hypothalamus of the rat (Durden and Boulton, 1982). The use of an alternative fragmentation mode such as negative chemical ionization employing methane yielded a dramatic (5,000 fold) increase in sensitivity for the pentafluorobenzyl ester of PAA due to reduced background (Faull and Barchas, 1983).

5.

Phenylacetic

Acid

Concentrations

PAA is found in most peripheral body fluids as a conjugate combined with glutamine to form phenylacetylglutamine (Goodwin et al., 1975). From Table 3, in the urine most PAA exists as All three groups who have measured PAA have measured very consistent amounts the conjugate. in the plasma as well as the urine. In the CSF, similarly, half the PAA exists as a conjuKaroum et al (1984) have measured urinary PAA in various psychiatric patients. gate. They suggested that while ingestion of PE leads to an increase in PAA excretion, an observation first made by Davis and Boulton (1980), the use of monoamine oxidase inhibitors did not reduce PAA excretion. Several other reactions may contribute to the amount of PAA excreted, The relative contribution of PE deamination to the total PAA concentrations in the rat or mouse brain has yet to be determined.

Effect

of drugs on phenylethyknine

Table Phenylacetic

acid

3

concentrations

in

Samp 1e

Human Plasma

Monkey

various

body

fluids

Concentration

Human Urine

Plasma

(Congugated) (Uncongugated) (Congugated) (Uncongugated) (Congugated)

120

(Non-Fasting) (Fasting) (Non-Fasting) (Non-Fasting)

Total Total Total Total

(M.

Mulatta)

Total

Fluid

Free Total Free

Human Cerebrospinal

493

28.7

mg/24

Reference

hr.

Goodwin

et

al

(1975)

0.9 129 8.4

Martin

et

153

Davis

and

ng/ml 416

Sandler et al (1979) Davis et al (1982)

383 459

Karoum

et

al

(1983)

839

Karoum

et

al

(1983)

ng/ml

Sandler et al (1979) Karoum et al (1983) Beckmann et al (1982)

42 24

(Congugated) Monkey

611

metabolism

al

(1979)

Boulton

(1980)

23 Tota 1

84

6.

Drug

Karoum

et

al

(1983)

Effects

The main drug effects upon PE concentrations were produced by increasing the precursor of or by inhibiting monoamine oxidase (MAO) by an inhibitor such as PE, namely phenylalanine, pargyline (Edwards and Blau 1973; Saavedra 1974), NSD-1055, an inhibitor of the central decarboxylase, prevented the increased PE concentrations normally formed when phenylalanine and pargyline were administered (Saavedra 1974) thus confirming that PE is formed by decarboxylation of phenylalanine in the rat brain. Pargyline greatly increased PE concentrations (Durden and Philips 1980) thus demonstrating that PE was rapidly metabolized in vi vo. a MAO-B inhibitor, produced an elevated concentration of rat brain PE at Deprenyl, much lower concentrations than did a MAO-A i nhi bi tor (Phi 1 i ps and Boul ton, clorgyl ine, 1979). One current area of controversy involves the effects of amphetamine on PE concentrations in the rat brain. Danielson et al (1976) reported no effect of either acute or chronic amphetamine treatment (5 mg/kg 30 min or 14 days treatment) on PE concentrations in the striatum, olfactory tubercles, hypothalamus or hippocampus of male Wistar rats. In cant rareported an increase in the hypothalamus and caudate distinction, Karoum et al (1981) nucleus of the rat after chronic treatment. This difference may be due to methodology or to the unique intragastric route of administration employed by the latter investigators.

7.

Effects

on

Other

Neurotransmi

tters

and

Neuromodulators

A number of workers have suggested that PE influences the dopaminergic system by affecting In an electrophysiological study, PE potentiated DA concentrations (Jonsson et al., 1966). the depression in cell firing rate produced by dopamine when both were simultaneously applied to spontaneously firing caudate neurons (Jones and Boulton, 1980). In an in vitro system, PE was shown to increase the efflux of labelled DA from the rat ventricular system the releasing effect of PE on DA was established by (Baker et al., 1976). Recently, measurement of the increased DA concentration in the perfusate of a push-pull cannula placed in the rat caudate nucleus (Philips and Robson, 1983). Further evidence for the releasing effects of PE was the rapid increase in rat striatal 3-methoxytyramine concentrations observed after an intraperitoneal injection of a 12.5 mg/kg dose of PE (McQuade and Wood, The subsequent sequence of changes in dihydroxyphenylacetic acid concentration, 1983).

P. S. McQuade

612

homovanillic amine very

acid concentration effectively releases

and finally in DA concentration dopamine into the synaptic cleft.

suggest

that

phenylethyl-

Whole brain concentrations of NE are decreased to 82% of control after an acute dose of PE (80 mg/kg) (Slovi ter et al., Twenty min after an acute dose of PE (20 mg/kg) NE 1980). . concentrations in the rat caudate nucleus were increased while in the hypothalamus they were decreased (Karoum et al., 1982). Chronic administration of PE (100 mg/kg; intragastrically) increased both NE concentration and that of its principal metabolite, 3-methoxy4-hydroxyphenylglycol, in the hypothalamus. Interestingly this chronic treatment also elevated NE concentration in the nucleus accumbens (Karoum et al., 1982). A single injection of syndrome identified as consisted of a resting rhythmic dorso-ventral I ateral head weaving. treatment (Sloviter et brain 5-HT concentrations

PE (50 mg/kg) or 7 daily injections of PE produced a behavioral being due to 5-Hi release or receptor stimulation. This syndrome tremor, rigidity or hypertonicity, reciprocal forepaw padding movement of the forelimbs, hindlimb abduction, Straub tail and Al 1 these symptoms were abol ished by mianserin and methysergi de al., 1980; Dourish, 1981). Sloviter et al (1980) claimed that whole were not affected by PE (80 mg/kg) 10 minutes post injection.

PE at doses of I50 mg/kg or 200 mg/kg induced convulsions in mice 11 to 12 min after injection which could be completely antagonized by chlordiazepoxide or diazepam. This suggested that at very large doses PE affects central GABAergic transmission (Cooper and Dourish, 1983). In contrast, Korpi and Wyatt (1983) could find no changes in the aspartate, glutamate, glutamine, alanine, taurine or GABA concentrations in the hypothalamus or caudate of adult Sprague-Dawley rats injected intragastrically with phenylethylamine (100 mg/ After chronic intragastric injection of PE (100 mg/kg twice daily for 10 days), kg) . taurine concentrations in both the caudate and hypothalamus were reduced. The acute administration of PE (50 mg/kg; subcutaneously) to mice produced an initial decrease in para-tyramine concentrations in the caudate nucleus at 0.5 hr but by 2 hr synthesis of para-tyramine had become apparent (McQuade and Juorio, 1982). Meta-tyrami ne concentrations increased at I and 8 hr. A bimodal increase in the acid metabol i tes of both tyramines appeared with the first peak observed at 0.5 hr to 1 hr after PE administration and the second peak appearing at 4 hr. This bimodal effect was further investigated by inThis treatment produced an increase in the jecting deuterated PE (McQuade and Wood, 1983). nondeuterated p-hydroxyphenylacetic acid and m-hydroxyphenylacetic acid concentrations by 0.5 hr after administration reflecting the release of the endogenous tyramines. The deuterated acid increased by 2 hr reflecting synthesis of the tyramines from deuterated PE. Cascio and Kellar (1983) first rat cortical membranes. PE had amine (2.4); 5 methyltryptamine upon r3H]tryptamine binding was was not as effective.

described the effect of PE upon [3Hjtryptamine binding in an inhibition constant of 87 nanomolar, following trypt(16) and tetrahydro-a-carboline (28). This effect of PE study also confirmed by Wood et al (in press ) but in this

8.

Concl us ions

compounds wh i ch can Phenylethylamine and its deaminated metabol ite, PAA, are endougenous be measured by using such selective, specific and sensitive techniques as GC, and GC-MS. PE is found in rat brain at concentrations of l-2 ng/gm wet tissue whi II e PAA is found at __-_ . 20-30 times this concentration. While at least two reactions contribute to peripheral body fluids PAA concentrations, the effects of the administration of the amino acid precursor to PE, phenylalamine or inhibition of PE deamination produce striking increases in endogenous PE concent rat ions. PE appears to act indirectly possibly serving as an endogenous fine control mechanism for DA, NE or 5-HT neurotransmission. References ALLES, G.A. (1933) The comparative physiological actions of dl-a-phenylisopropylamines. I. Pressor effect and toxicity. J. Pharmacol. Exp. Ther. 47: 339-354. BAKER, G.B., RAITERI, M., BERTOLLINI, A., DEL CARMINE, R., KANE, P.E. and MARTIN, I.L. (1976) Interaction of B-phenethylamine with dopamine and noradrenaline in the central J. Pharm. Pharmacol. 28: 456-457. nervous system of the rat. REYNOLDS, G.P., SANDLER, M., WALDMEIEK P., LAUBER, J., RIEDERER, P. and BECKMANN, H., GATTAZ, W.F. (1982) Phenylethylamine and phenylacetic acid in CSF of schizophrenics

and

Effect

healthy CASCIO, brain.

controls. C.S.

and

Eur.

J.

Arch.

KELLAR,

of

Psychiatr.

K.J.

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on phenylethylamine

Nervenkr.

232:

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613

metabolism

463-471. of

[3H]tryptamine

binding

sites

in

31-39.

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614

P. S. McQuade

cerebrospinal fluid concentrations Chromat. Sci. 21: 546-550. KAROUM, F., POTKK, S., CHUANG, L.W.,

of

phenylacetic

acid

in

humans

and

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