Another look at the monoamine oxidases and the monoamine oxidase inhibitor drugs

Life Sciences Vol . 14, pp " 2061-2074 Printed in II .S .A .

Pergamon Press

1QNIREVIE9P

ANOTHER LOOK AT THE MONOAMINE OXIDASES AND THE MONOAMINE OXIDASE INHIBITOR DRUGS . N . H. Neff and H .-Y. T . Yang Laboratory of Preclinical Pharmacology, National

Institute of Mental

Health, Saint Eltzabeths Hospital, Washington, D. C . 20032 Drugs that Inhibit monoamine oxidase (MAO ; moraamins: tase (deamtnating) EC 1 .4 .3 .4) have proven useful sloe and of mild to moderate hypertension . Itor drugs by pharmaceutical

oxygen oxidoraduc-

in the treatment of depress-

The development of new MAO Inhtb-

Industry has almost been abandoned because of the

toxic effects of the original hydrazine and hydrazine drugs .

They produced

hepatotoxicity, impaired red-green color vision and neurologtc damage (1,2) . These toxic reactions were unrelated to the ability of these compounds to inhibtt MAO (3) . sided .

Nevertheless interest to this area of pharmacology has sub-

The ma]or complication associated with the few MAO Inhibitor drugs

that are currently used is a hypertensive episode following the Ingestion of foods containing high concentrations of amines, particularly tyramine (4) . Apparently the Ingested amines enter the circulation and because they cannot be metabolized by the liver,

they are free to release norepinephrtne from

nerve endings, thereby producing a hypertensive reaction . During the past several years multiple forms of MAO have been in vitro and in vivo .

identified

These enzymes appear to be localized In specific tis-

sues, apparently have preferred substrates and can bn inhibited differentally with drugs .

The purpose of this minirevtav Is to present a syrapsis of these

observatio ns . a more rational

Hopefully the presentation of these developments will

lead to

approach when administering MAO inhibitor drugs to man, and

to renewed Interest

in developing more specific and less toxic drugs .

For a

morecomprehensive evaluation of MAO research the reader is referred to a re2061

2062

Monoamine Oxidasea and Inhibitor Drugs

Vol. 14, No . 11

cent symposium (5) and the following reviews (6-8) . SEPARATION OF MULTIPLE FORMS OF MAO BY ELECTROPHORESIS Youdlm and Sandier (7, 9) were among the first to report that MAO of rat tissues could be separated Into several bands of activity by polyacrylamideOther investigators, studying various tissues In other

gel electrophoresis .

species, found several forms of MAO also using electrophoresic techniques (1014) .

One form of enzyme found on electrophoresis has been designated as "dopa-

mine MAO" because it desminated dopamine at a faster rate than

tt deamlnated

other amines, and the Km for dopamine was lower than for most other substrates (7) .

In addition, this enzyme was not inhibited by drugs that readily blocked

other forms of the enzyme and tt was more thermostable than the others .

At

pH 8 .4, "dopamine MAO" had a net positive charge whereas the other enzymes had a net negative charge .

Originally the term isozyme was used to describe the

various bands of enzyme activity implying that they were the consequence of a genetically determined difference In primary structure (15) . Houslay and Tipton (16)

proposed

Recently

that the multiple enzymes found on polyacryla-

mide-gel electrophoresis might be artifacts that result during the preparation of the enzyme .

For example,

they showed

that the MAO reported by Youdtm et al .

(l7) to remain on the surface of the gel was only present when the enzyme preparation was mixed with Sephadex G 200 before electrophoresis . Tipton (16)

proposed

Houslay and

that this form of the enzyme was an artifact of the

loading method and was probably due to aggregation or precipitation of the enzyme when

It was mixed with dry Sephadex .

Moreover they found that treatment

of a partially purified enzyme preparation (17) with perchlorate, phosphollpid before electrophoresis, activity .

resulted

to remove

to a single band of enzyme

Furthermore they were unable to detect a specific "dopamine MAO" .

As a consequence of these studies Houslay and Tipton (16) concluded that the multiple forms of MAO may represent a single enzyme protein with different amounts of attached phosphollpid and that the phosphollpid may govern the en-

Vol. 14, No . 11

2063

Monoamine Ozidaaea and inhibitor Druge

zyme's mobility during electrophoresis .

However, Houslay and Tiptop (16)

lost

more than half of the MAO activity during their purification procedure which might indicate that labile forms of the enzyme are lost during the preparation of the enryme and not that there is a single species of enzyme .

Although the

nature of the multiple forms of the enzyme is controversial, studies of the phospholipid associated with MAO might lead to the molecular explanation for the substrate and inhibitor specificity observed

In vitro and In vivo for the

enzyme . THE USE OF SELECTIVE SUBSTRATES AND DRUGS TO DEMONSTRATE MULTIPLE FORMS OF MAO . Many workers have postulated that multiple forms of MAO exist In vtvo , based on substrate and Inhibitor studies, and that not all forms of the enzyme are found In all tissues (18) .

In 1968, Johnston (19)

Introduced the

drug clorgyline (M b B 9302, N-methyl-N-propargyl-3- (2,4-dtchlorophenoxy) propylamine hydrochloride) and he demonstrated that the drug could be used to Identify multiple forms of MAO in brain .

Johnston (19) showed that there was

a stepwise inhibition of MAO activity when homogenates were pretreated with Increasing concentrations of clorgyline prior to adding the substrate tyramine . To account for this, he postulated that there were two forms of enzyme in brain ; an enzyme sensitive to clorgyline and an enryme resistent to clorgyline . He designated the enryme sensitive to clorgyline as enzyme A and the resistent form as enzyme B .

We will

call them Type A and Type B enzyme as there Is evt-

dente that they may represent classes of enrymes with similar characteristics rather than single enzymes (20) .

At high wneentrations of clorgyline all

enzyme activity is blocked (19) .

Johnston (19)

found that serotonin was a

preferred substrate for Type A MAO and Hall et al . (21) was a preferred substrate for Type B MAO .

found that benzylamine

One of the endogenous preferred

substrates for Type B enzyme is most likely ß -phenylethylamine (22) . mine was a substrate for both enzymes (19) .

Hall et al .

(21)

Tyra-

subsequently

2064

Vol . 14, No . 11

Monoamine Oxidases and Inhibitor Drugs

showed that clorgyline could be used to demonstrate the presence of multiple enzymes in several species, has been detected In swine. McCauley and Rocker (23)

but not to all species .

Only one form of enzyme

In support of Johnston's original proposal,

recently reported that they could distinguish between

MAO A and MAO B by their antigenic properties . The list of preferred substrates and specific inhibitor drugs has grown since 1968 when Jahnston Introduced clorgyline (Table 1) . TABLE 1 SOME

INHIBITOR DRUGS AND SUBSTRATES OF TYPE A AND B MONOAMINE OXIDASE

Monoamine Oxidase Type A Preferred Substrates

Serotonln Norepinephrine Normetanephrine

Specific Inhibitor Drugs

Clorgyline Lilly 51641 Harmaline

Common Substrates

Type B Benzylamine ß-Phenylethylamine

Deprenyl

Dopamine Tyramine Tryptamine

Nonspecific Inhibitor Drugs

*Pargyllne Isocarboxazid Phenelzine Ipronfazid

* May preferentially inhibit Type B enzyme .

Tranylcypramine Nialamide Phenlprazine Compiled from References 18 .19 .

21, 22, 30 and 31 . When one type of enzyme

is

Inhibited at lower concentrations of drug then the

other type of enzyme, the drug is designated as specific (relatively specific) . When the same concentration of drug is required to inhibit both types

Vol. 14, No . 11

2065

efonoaaiine Oxidaae~ and inhibitor Dzugo

of enzyme, the drug is designated as nonspecific .

For example, deprenyl

In-

hibits Type B enzyme at a lower concentration than is required to Inhibit Type A enzyme (24) .

Generally, all enzyme activity Is blocked when the drugs

are present at high concentrations . preferred or conmon substrates .

Substrates are llated

In Table 1 as

Common substrates are metabolized by both

types of the enzyme whereas preferred substrates are metabolized by one form of the enzyme .

For example,

tyramine is metabolized by both enzymes (19),

whereas ß-phenylethylamine is metabolized by Type 8 enzyme (22) . Almost all of the drugs that have been used clinically apparently block both enzymes ; they are nonspecific drugs .

The therapeutic effects associated

with MAO inhibitor drugs are usually ascribed to the Interruption of the metabolism of the transmitter amines .

Noropinephrine (25) and serotonin (19) are

oxtdatlvely designated by Type A enzyme and not by Type B enzyme .

Therefore,

a more rational therapeutic approach would be to administer a drug that specifically blocks Type A enzyme and not a drug that blocks all enzyme activity as has been done In the past .

SOME PROPERTIES OF THE MAO'S Phenylethylamines and Indolethylamtnes appear to be the endogenous substrates for tissue MAO.

The m-0-methylated catecholamtne metabolites have lower !tm

values than the parent amines (25) .

As shown in Table 1, normetanephrlne is a

proferred substrate for MAO A as Is norepinephrine (25) .

Oxygen

is atso a

required substrate and flavin-adenine dinucleotide is found In most MAO's (27,28) .

The Wn value for oxygen Is about 0 .2 mM, which is about the concen-

tration of air saturated water at physiological temperature, enzyme normally works at less than maximal velocity (26) .

Implying that the

Tipton (26) has

shown, however, that as the concentration of oxygen is decreased the Km value for amines also decreases .

Thus, the relative efficiency with which the enzyme

oxidizes low concentrations of amine increases as the oxygen concentrations fall

rendering the enzyme relatively insensitive to large fluctuations of local

2066

Vol . 14, No . 11

Monoamine Oxidasea and inhibitor Druga

oxygen concentrations . The molecular weight of the enzymes appears to be about 10 5 , but the enzyme may aggregate producing apparent weights of up to 10 6 (6) . (29) and phospholipid (16) are found in same preparations of MAO .

Carbohydrate Tipton (6)

has speculated that the preparations of MAO prepared thus far may not represent pure protein and Housley and Tipton (16)

suggest that phospholipid

associated with the enzyme may be responsible for the multiple forms of MAO found by polyacrylamide-gel electrophoresis .

The presence of phospholipid

may explain many of the other properties of the enzyme as well . When crude preparations of MAO (22,30) or MAO prepared by polyacrylamidegel electrophoresis (17)

are subJected to high temperatures and then tested for

activity, a multiphaslc loss of activity is observed suggesting the existence of multiple forms of the enzyme .

By using specific

Inhibitor drugs and sub-

strates tt appears that MAO B is more sensitive to heat than MAO A (22,31) . The thermostabiltty of the enzymes might be a useful nature of the enzymes .

indicator of the molecular

Oreland and Ekstedt (32) demonstrated that the thermo-

stabllity of MAO preparations was dependent on the presence of phospholipid . The thern~ostability of many enzymes is

Influenced by the chemical

environment surrounding the enzyme protein.

nature of the

For example, enzymes bound to

hydrophilic solid supports are more heat stable than when bound to hydrophobic supports (33) . (31) .

MAO A is readily digested by trypstn when compared with MAO B

Oreland and Ekstedt (32) found that removal of phospholipid from MAO

rendered the enzyme more sensitive to trypsin .

Balleau and Morgen (34)

suggest-

ed that the aromatic moiety of Inhibitor drugs and substrates Interact with nonspecific sites on the enzyme surface and not with the actual catalytic sites . These observations taken together suggest that phospholipid may constitute or influence the nonspecific sites and thus be responsible for the formation of the various forms of MAO from enzyme protein with the same catalytic sites . Perhaps, MAO B contains more phospholipid than MAO A and Is, therefore, more hydrophobic than MAO A.

Monoamine O:idasas and inhibitor Druge

Vol . 14, No . 11

2067

The chemical naturo of the substrates and inhibitor drugs is consistent with the properties Just described.

Serotonln, norepinephrine and clorgyline

(substances that Interact with MAO A) have more polar aromatic rings than benzylanlne, ß-phenylethylamine and deprenyl MAO B) .

In general,

(substances that interact with

adding a polar hydroxyl group to ß-phenylethylamine

(tyranine) or removing one from serotonin (tryptanine) produces a common sub strate .

In view of the Importance of the phospholipid for enzyme activity, a

purified solubilized enzyme removed from its environment may not have the sane characteristics as the enzyme in vivo . LOCALIZATION OF THE MAO'S MAO is present in most organs, and tt is associated with the outer mltochondrlal membrane (35) .

In the liver, there is evidence that a small fraction of

MAO may be associated with the microsames (36) .

Previously there was suggest-

ive evidence that neuronal MAO might be associated with the amine storage granules, however,

these studies were re-evaluated and it

Is now accepted that

MAO is located en mitochondria In neurons and that during homogenization some enzyme is released (37) .

The observation that homogenization could release

MAO from the mitochondria of same tissues and not others Implies that mitochondria are probably not homogeneous and, heterogenity .

Indeed, there Is evidence for

For example, mitochondria from glial cells and from neuronal

cells from rabbit brain have different buoyancles (38) . activities of several enzymes varies

Furthermore, the

in different populations of mitochondria

(39), Including the activities of Type A and B MAO (22) .

More MAO B activity

is associated with mitochondria of high buoyancy than with mitochondria of low buoyant density (22) . The presence or absence and the type of MAO appears to be, in part, governed by the amines found In tissues .

For example, Consolo et al . (40)

reported

that there was virtually no MAO actJvlty to some cholinergtc neurons . sympathetic nerves that Innervate the pineal gland (41), the mesenteric

The

2068

Vol. 14, No . 11

Monoamine Oxidases and inhibitor Drugs

arteries (42) and the vas deferens (43) all contain MAO A primarily,

the

enzyme that metabolizes norepinephrlne (25) . The presence of a particular amine in a tissue Is not always an that the "proper" MAO will

be present in the tissue .

indication

Serotonln is found in

the rat pineal gland where It is an intermediate for melatonin (5-methoxyN-acetyltryptamine) (44) . Is the predominant enzyme

Type B enzyme, which is not active toward serotonin, in the pineal gland thereby assuring that serotonin

will be available for the formation of melatonin (44) .

The highest concen-

tration of ß-phenylethylamine, width is a preferred substrate for Type B MAO, In brain is found in the pineal these observations

gland (45) .

The physiological significance of

remains to be explored .

The presence of Type A MAO to sympathetic neurons and its absence In same postsynaptic sites,

such as the pineal parenchymal cells,

is consistent with

the hypothesis that oxidative deamination (46) of norepinephrlne takes place within neurons and not at receptor sites . In rat and human brain, A and (unpublished observation) .

e

MAO appear to be uniformally distributed

Presently there is no direct evidence to suggest

that MAO A is localized in noradrenerglc or serotonergic neurons,

but apparent-

ly MAO A is responsible for the metabolism of norepinephrlne and serotonin In vivo .

Administering a selective inhibitor of MAO A to rats induces an eleva-

tion of serotonin and norepinephrlne tive

In brain (47,48) .

Administering a selec-

inhibitor of MAO B has no effect on the metabolism of these amines .

Dopamine, to contrast to norepinephrlne and serotonin, A as well as MAO B (48) .

is metabolized by MAO

As a consequence, dopamine metabolism Is curtailed

along with that of norepinephrlne and serotonin after blocking MAO A.

However,

only dopamine metabolism is modified following treatment with a drug that blocks MAO 8 (48) . HUMAN PLATELET MAO Blood platelets have many biochemical similarities and, therefore,

In common with neurons

they are often studied in man as an alternative to studying

the brain .

2069

Monoamine Ozidases aad inhibitor Drugs

Vol . 14, No . 11

In animals,

the degree of inhibition of platelet W40 following the

administration of drugs is directly correlated with the Inhibition of brain MAO thus providing some evidence that MAO activity In human platelets may reflect MAO activity of brain following drug troatment (49) .

However, platelet MAO

does not appear to have the same characterlatics as brain MAO.

Platelet MAO

shows only a single band of activity following polyacrylamide-gel electrophorosis (50) and the enzyme appears to behave more like Type B enzyme than Type A enzyme (49) .

Type A enzyme Inactivates the putative transmitters In

brain . Recently, reduced MAO activity of platelets has been observed in bipolar depression (51) end schizophrenia (52,53) .

Moreover, ,plate let MAO activity has

been suggested es a possible genetic marker for vulnerability to schizophrenia (53) .

At prosent there are no reports of a decrease of MAO In brain of such

subJects at postmortem examination .

Considering that brain Is composed pri-

marily of glla it Is doubtful that any changes of MAO in neurons would be observed

in samples of brain unless there was almost complete loss of enzyme

from neurons .

The significance of decreased platelet MAO to brain biochemistry

will require clarification .

Now that we can separate neuronal cell bodies

from gllal cells by microdissectlon and by density gradient centrifugation such inforniation may be forthcoming (38,54) . THE CONSEQUENCES OF ADMINISTERING SPECIFIC MAO INHIBITOR DRUGS ON A!lIINE METABOLI$M IN BRAIN Thus far we have presented evidence that multiple forms of MAO can be identified in animal

and hwnan tissues when tested in vitro, that these enzymes

have proferred substrates and that they can be inhibited selectively with drugs . These observations are of little clinical firmed

In vivo and,

indeed, they can (48) .

clorgyline can be predicted from Table 1 . MAO A,

Importance unless they can be conThe consequences of infecting There Is a proferential blockade of

and serotonin, noropinephrine and dopamine Increase In brain .

Serotonin

Monoamine Oxidasea and Inhibitor Drugs

2070

Vol . 14, No . 11

and norepinephrine are preferred substrates for MAO A while dopamine Is a substrate for both enzymes . hibitor of MAO B,

Following the inJectlon of deprenyl, an in-

there is an increase of dopamine in brain, but not of

serotontn or norepinephrine . for MAO B .

Serotonin and noreptnephrlne are not substrates

In suppport of the view that clorgyline and deprenyl act on sepa-

rate enzymes in vtvo . 5-hydraxyindoleacetic acid (serotontn metabolite) and 3,4-dihydroxyphenylacetic acid (dopamine metabolite) are decreased after treatment with clorgyline whereas only 3,4-dihydroxyphenylacetic acid creased after deprenyl treatment (48) .

is de-

These studies provide clear evidence

that the multiple forms of enzyme identified in vitro exist in vivo . CONCLUSIONS MAO Inhibitor drugs are currently used to treat hypertension and to alleviate depression .

Although their mechanism of action is unclear, modified amine

metabolism is presumed to be responsible for their activity .

Blockade of MAO

to peripheral neurons is probably responsible for the effect on blood pressure while blockade of MAO in brain is probably responsible for the antidepressant activity .

The observation that there are multiple forms of MAO, that these

enzymes metabolize different amines and that sympathetic neurons contain Type A enzyme are essential factors to be considered for therapy or when developing new drugs . For antihypertensive activity, administering drugs that specifically block Type A MAO should produce the desired therapeutic effect while producing fewer potential side effects .

Furthermore, there is now information available on

how to limit the penetration of MAO inhibitor drugs into brain (55,56) and on the structural

requirements necessary for the accumulation of drugs In sym-

pathetic

neurons (57-57) .

approach

when developing new MAO Inhibitor drugs to treat hypertension .

Clearly the stage is set for a more sophisticated

The transmitter amines, dopamine, noreptnephrlne and serotontn, are assumed to modulate mood, and the antidepressant effect of the drugs that inhibit MAO

vol . 14, No . 11

eon

Monoamine Oxidaaes and inhibitor Druge

may be the consequences of delaying the metabolism of these amines . amines are deaminated by MAO A and,

thereforo,

compounds that block MAO A specifically .

All three

the drugs of choice would be

Administering nonspecific drugs

might possibly increase side effects without producing the desired pharmacologic response . dopamine

If the desired pharmacologlc response Is to elevate only

In brain then the therapy of choice would be to administer an In-

hibitor of MAO B .

Such drugs may be useful for treating Parkinson's disease

especially If they are combined with L-Dope therapy. MAO Inhibitor drugs may be useful

Furthermore, selective

tools for evaluating the physiological roles

that have been ascribed to the various amines of brain . Most of the studies on which these conclusions are based were performed in animals or on animal tissues. 11ver (15 ), pineal gland (60)

The enzymes of human sympathetic nerve (60), and brain (7, and unpublished observations) are

similar to the enzymes found 1n most animals .

It remains to be determined

if

the rosults obtained by administering drugs to animals can be extrapolated to man,

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Monoamine Oxidasea and Inhibitor Druga

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