Rebecca Graumann et al- Oxidation of Dopamine to Aminochrome as a Mechanism for Neurodegeneration of...

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OXIDATION OF DOPAMINE TO AMINOCHROME ASA MECHANISM FOR NEURODEGENERATION OFDOPAMINERGIC SYSTEMS IN PARKINSON’S DISEASE.POSSIBLE NEUROPROTECTIVE ROLE OF DT-DIAPHORASE

Rebecca Graumann, Irmgard Paris, Pedro Martinez-Alvarado, Pamela Rumanque, Carolina Perez-Pastene, Sergio P. Cardenas, Pablo Marin,

Fernando Diaz-Grez, Raul Caviedes, Pablo Caviedes, Juan Segura-Aguilar

P r o g r a m m e o f M o l e c u l a r a n d C l i n i c a l P h a r m a c o l o g y , I C B M , F a c u l t y o f M e d i c i n e , U n i v e r s i t y o f C h i l e ,

I n d e p e n d e n c i a 1 0 2 7 , C a s i l l a 7 0 0 0 0 , S a n t i a g o 7 , C h i l e

Oxidation of dopamine to aminochrome as a mechanism for neurodege-neration of dopaminergic systems in Parkinson’s disease. Possible neuropro-tective role of DT-diaphorase. R. GRAUMANN, I. PARIS, P. MARTINEZ-ALVARADO, P. RUMANQUE, C. PEREZ-PASTENE, S.P. CARDENAS,P. MARIN, F. DIAZ-GREZ, R. CAVIEDES, P. CAVIEDES, J. SEGURA-AGUILAR. Pol. J. Pharmacol., 2002, 54, 573–579.

Although it is generally accepted that free radicals are involved in theneurodegenerative process occurring in the dopaminergic neurons of the ni-gro-striatal system in Parkinson’s disease, the exact mechanism of neurode-generation in vivo is still unknown. We propose that the degeneration of do-

paminergic nigrostriatal system in this condition may depend on: (a) exis-tence of free dopamine which oxidizes to aminochrome as a consequence of:(i) overproduction of dopamine; (ii) inhibition and/or low expression of syna-

ptic vesicle catecholamine transporter; (iii) inhibition or low expression of monoamine oxidases; (b) one-electron reduction of aminochrome to leuko-aminochrome o-semiquinone radical, which induces neurotoxicity, due to in-hibition of DT-diaphorase or the existence of a polymorphism with a pointmutation (C ® T) in the cDNA 609 expressing an inactive DT-diaphorase. Wesuggest that DT-diaphorase plays a neuroprotective role in dopaminergic neu-rons, which is supported by the following observations: (i) Cu-toxicity is de-

pendent on DT-diaphorase inhibition with dicoumarol in RCSN-3 cells derived

from the rat substantia nigra; (ii) the cytotoxic effect of monoamine oxidase-Ainhibitor amiflamine in RCSN-3 cells is increased by 2.4-fold (p < 0.001) in the

presence of the inhibitor of DT-diaphorase, dicoumarol; (iii) concomitant in-tracerebral administration of manganese (Mn 3 + ) together with the DT-dia-

phorase inhibitor dicoumarol into the left medial forebrain bundle produceda behavioral pattern characterized by contralateral rotational behavior whenthe rats were stimulated with apomorphine, in a manner similar to that ob-served in animals injected unilaterally with 6-hydroxydopamine; (iv) incu-

bation of RCSN-3 cells with salsolinol in the presence of DT-diaphorase in-hibitor significantly decreased cell survival by 2.5-fold (p < 0.001).

Key words: dopamine, neurotoxicity, Parkinson’s disease, DT-diaphorase

C o p y r i g h t © 2 0 0 2 b y I n s t i t u t e o f P h a r m a c o l o g y

P o l i s h A c a d e m y o f S c i e n c e s

P o l i s h J o u r n a l o f P h a r m a c o l o g y

P o l . J . P h a r m a c o l . , 2 0 0 2 , 5 4 , 5 7 3 5 7 9

I S S N 1 2 3 0 - 6 0 0 2

correspondence; e - m a i l : j s e g u r a @ m a c h i . m e d . u c h i l e . c l



Abbreviations: DAT – dopamine transporter,ESR – electron spin resonance, Gamma-GT – gamma-glutamyl transpeptidase, GSH – reduced glutathione, GSSG – oxidized glutathione, GST – glutathione transferase, MAO – monoamine oxi-

dase, VMAT – vesicular monoamine transporter

INTRODUCTION

Parkinson’s disease is characterized by degen-eration of the nigrostriatal dopaminergic system,which has an important role in the control of motor and associative functions. Although it is generallyaccepted that free radicals are involved in the neu-rodegenerative process of Parkinson’s disease whichtakes place in the dopaminergic nigrostriatal neu-

ronal system [14], the exact mechanism of neuro-degeneration in vivo is still unknown. One possiblesource of free radicals may involve oxidation of dopamine to neuromelanin. Formation of neurome-lanin is a normal process in the substantia nigrawhich involves several steps: (i) dopamine oxida-tion to dopamine o-quinone catalyzed by metals,oxygen, peroxynitrite or enzymes such as prosta-glandin H synthase, cytochrome P450 1A2, xan-thine oxidase, tyrosinase, dopamine b-monooxyge-nase [8–12, 14, 21, 24, 32]; (ii) cyclization of dopa-mine o-quinone to aminochrome via an addition

reaction at physiological pH values, leading to theformation of leukoaminochrome and oxidation of leukoaminochrome to aminochrome [16]; and (iii)

polymerization of aminochrome to neuromelanin[30]. Dopaminergic neurons, which synthesize do-

pamine and express dopamine re-uptake transport-ers (DAT), have very powerful mechanisms to pre-vent oxidation of dopamine. The first of them con-sists in incorporation of dopamine into vesicles (for neurotransmission) which have a low internal pHvalues, that stabilizes catechol structure and con-fers resistance to oxidation since protons are very

strongly bound to oxygen atoms in the molecule. Neuromelanin synthesis was abolished in PC12 cellswith adenoviral-mediated overexpression of the sy-naptic vesicle catecholamine transporter (VMAT2),

by increasing dopamine accumulation in the vesi-cles and decreasing free cytosolic dopamine [31].The second mechanism involves dopamine me-tabolism by monoamine oxidase (MAO). An in-crease in dopamine synthesis and saturation of VMAT and/or MAO metabolism or low expressionof VMAT /MAO enzymes would generate an in-

crease in free dopamine which at physiological pHwould autoxidize to form neuromelanin. However,aminochrome metabolism is not only restricted to

polymerization to form neuromelanin since amino-chrome can be conjugated with GSH and reduced

by one- or two-electron transfer catalyzed by qui-none reductases.

ONE-ELECTRON REDUCTION

OF AMINOCHROME

Aminochrome can undergo one-electron reduc-tion by flavoenzymes which receive electrons from

NADPH or NADH. NADPH-cytochrome P450 re-ductase has been used as a model enzyme for one-electron quinone reductases [2, 27]. This enzyme is

a flavoenzyme which transfers electrons from NADPH to cytochrome P450, but it can also transfer electrons to cytochrome C and quinones. NADPH-cytochrome P450 reductase catalyzes one-electronreduction of aminochrome to leucoaminochromeo-semiquinone. The continuous NADPH oxidationand oxygen consumption reveals the ability of leu-koaminochrome o-semiquinone to autoxidize inthe presence of oxygen [2] (Fig. 1). Leukoamino-chrome o-semiquinone undergoes autoxidation byreducing oxygen to superoxide radicals giving riseto redox cycling, which persists until NADPH or oxygen is depleted. It is interesting to point out thatvery low concentrations of aminochrome can pro-duce a large amount of reactive oxygen species dueto its ability to enter redox cycling. Depletion of

NADPH will result in oxidized glutathione (GSSG)accumulation and reduced glutathione (GSH) de-

pletion which is an important antioxidant in thecell. However, other flavoenzymes may catalyzeone-electron reduction of aminochrome by oxidiz-

574P o l . J . P h a r m a c o l . , 2 0 0 2 , 5 4 , 5 7 3 5 7 9

R. Graumann, I. Paris, P. Martinez-Alvarado, P. Rumanque, C. Perez-Pastene, S.P. Cardenas,

P. Marin, F. Diaz-Grez, R. Caviedes, P. Caviedes, J. Segura-Aguilar

Red. 1e-

N

H

O

O

O 2

N

H

O

HO

NAD+

NADP +

O 2

NADH

NADPH

O 2H 2O 2

2H+

-Fe2+

/ Cu+

Redox cycling

OH + OH

Fig. 1. O x i d a t i o n o f d o p a m i n e t o n e u r o m e l a n i n



ing NADH to NAD+ . Depletion of NADH, whichnormally transfers electrons in the mitochondria,will prevent ATP formation.

The high reactivity of leukoaminochrome o-semi-quinone is supported by electron spin resonance(ESR) studies [27]. Dopamine oxidized by tyrosi-nase was used to perform ESR studies to detecto-semiquinone radical signal during one-electronreduction catalyzed by NADPH cytochrome P-450reductase. A mixture of two spectra containing leu-koaminochrome o-semiquinone and dopamine o-se-miquinone was obtained since dopamine o-quinoneis the precursor of aminochrome. NMR studiesshowed that 50% of reaction mixture during dopa-mine oxidation catalyzed by tyrosinase was dopa-mine o-quinone [27]. Of these mixtures of ESR

spectra only dopamine o-semiquinone spectra werestabilized and accumulated during 10 min. The sta-

bilized ESR signal after 10 min was exactly thesame as the ESR signal obtained during one-electronoxidation of dopamine to dopamine o-semiquinonecatalyzed by lactoperoxidase in the presence of hy-drogen peroxide [27]. Leukoaminochrome o-semi-quinone ESR signal was found to be very unstable

because only traces of this signal were detected after two minutes of incubation. These results representa strong evidence that NADPH cytochrome P450 re-ductase also catalyzes the one-electron reduction of dopamine o-quinone to dopamine o-semiquinone.The instability of leukoaminochrome o-semiquinonecontrasts with the stability of dopamine o-semiqui-none, suggesting that leukoaminochrome o-semiqui-none is the most reactive species formed during do-

pamine oxidative metabolism.Another important feature of leukoaminochro-

me o-semiquinone is that the removal of superoxi-de radicals and hydrogen peroxide present in theincubation mixture results in an increase in theautoxidation rate [2]. This increase can be ex-

plained by the possible competition between dioxy-gen (O

2

) and superoxide radicals and hydrogen per-oxide to react with the o-semiquinone. Therefore,the presence of superoxide dismutase and catalase,which remove both superoxide and hydrogen per-oxide radicals, will result in the increase in theautoxidation rate of leukoaminochrome o-semiqui-none. These results suggest a clear prooxidant roleof these antioxidant enzymes during one-electronreduction of aminochrome.

ANTIOXIDANT REACTIONS WHICH

PREVENT THE FORMATION

OF LEUCOAMINOCHROME

O-SEMIQUINONE RADICAL

Glutathione conjugation of aminochrome

We have found that glutathione transferasescatalyze the conjugation of aminochrome with glu-tathione [3, 22]. Glutathione transferases (GST-M2-2 and GST-M1-1) are the isoenzymes, whichexhibited the highest specific activity. During thisconjugation, aminochrome is reduced to leukoami-nochrome. Our results show that the formed leuko-aminochrome-GSH is stable in the presence of bio-logical oxidizing agents such as dioxygen, superoxideradicals and hydrogen peroxide [22]. The stability

of this conjugate contrasts with aminochrome re-duced forms (leukoaminochrome and leukoamino-chrome o-semiquinone) which undergo autoxida-tion by reducing oxygen to superoxide radicals. Itis of interest to note that both GST-M2-2 andGST-M1-1 inhibit the redox cycling process duringone-electron reduction of aminochrome catalyzed

by NADPH cytochrome P450 reductase by com- peting with NADPH cytochrome P450 reductase touse aminochrome as a substrate. These results sug-gest that reduction of aminochrome by GST-M2-2and GST-M1-1 may be an important antioxidant

reaction, preventing the redox cycling between oxi-dized and reduced states. We have cloned GST-M2-2 from a human substantia nigra cDNA library,thus demonstrating the expression of this enzymein the relevant region of the brain [3].

Glutathione conjugation of dopamine o-quinone

The precursor of aminochrome, dopamine o-qui-none is conjugated with GST-M2-2 to 5-S-gluta-thionyldopamine preventing the formation of ami-nochrome [7] (Fig. 2). The relevance of this reac-tion is that it prevents the metabolic reductive acti-vation of aminochrome to reactive oxygen speciesand leukoaminochrome o-semiquinone radical, whichmay be responsible of the observed toxic effects of dopamine. In addition, the conjugation of dopami-ne o-quinone to 5-S-glutathionyldopamine can bethe precursor reaction of 5-S-cysteinyldopamine. Inthe rat brain it has been demonstrated that 5-S-glu-tathionyldopamine conjugate is rapidly metabo-lized to 5-S-cysteinyldopamine in reactions medi-ated by gamma-glutamyl transpeptidase (gamma-GT)

I S S N 1 2 3 0 - 6 0 0 2

575

D T - D I A P H O R A S E : A N E U R O P R O T E C T I V E E N Z Y M E



and cysteine conjugate N-acetyltransferase [29].Therefore, it seems plausible that 5-S-glutathionyl-dopamine can be converted by gamma-GT and N-acetyltransferase to form 5-S-cysteinyldopamine.5-S-cysteinyldopamine has been detected in cere-

brospinal fluid of Parkinson’s disease patients andcontrol subjects [4, 6]. In the human brain, 5-S-cys-teinyldopamine has been identified in dopamine-rich brain regions such as the caudate nucleus, pu-tamen, globus pallidus and substantia nigra [5, 19].In addition to excretion, a pathway of 5-S-cyste-

inyldopamine incorporation into neuromelanin has been suggested. 5-S-cysteinyldopamine has beenreported to be the main source of the pheomelaninmoiety of human neuromelanin isolated from thesubstantia nigra [5]. The physiological relevance of GSH conjugation of dopamine o-quinone to 5-S-glu-tathionyldopamine as a neuroprotective reaction issupported by the finding that formation of 5-gluta-thionyl- and 5-S-cysteinyldopamine prevented do-

pamine-mediated DNA damage in a dose-depen-dent manner [18].

Two-electron oxidation of aminochrome cata-lyzed by DT-diaphorase

DT-diaphorase (E.C. 1.6.99.2, NAD(P)H: qui-none (menadione) oxidoreductase) is a unique en-zyme among flavoenzymes, and is mainly localizedin the cytosol (95%). However, around 5% is alsofound associated to the mitochondria and endoplas-mic reticulum. DT-diaphorase reduces quinones tohydroquinones by transferring two electrons, pre-venting the formation of semiquinone radical, andit is specifically inhibited by dicoumarol. DT-dia-

phorase is present in dopaminergic neurons, consti-tuting 98% of the total quinone reductase activity[20, 25]. DT-diaphorase catalyzes two-electron re-duction of aminochrome to o-hydroquinone (leu-koaminochrome) which also autoxidizes in the pre-sence of oxygen resulting in the formation superoxideradicals and hydrogen peroxide (Fig. 3). However,the autoxidation rate is very low compared to leu-koaminochrome o-semiquinone autoxidation rate.In addition, the chemistry of autoxidation of leu-koaminochrome was found to be completely differ-

576P o l . J . P h a r m a c o l . , 2 0 0 2 , 5 4 , 5 7 3 5 7 9



NH 2

OHNH

HN

NH 2OHO

OOO

HO

HO

NH2

HO

HO RNH 2O

O

O

ONH

O

HONH

HO

HO N

H

GSH

S

HOHN

NH

NH 2O

OH

O O O

S

-

O2

O2

GSH

Dopamine

Dopamine-o-quinone

4-S-glutathionyl-5-6-dihydroxyindoline

Aminochrome

5-S-Glutathionyl-dopamine / dopaNeuromelanin

5-S-Cysteinyl-dopamine / dopa

Cerebrospinalfluid

Neurotoxicity Fig. 2.G l u t a t h i o n e c o n j u g a t i o n o f d o p a m i n e

o- q u i n o n e a n d a m i n o c h r o m e



ent since superoxide radicals and hydrogen perox-ide are mainly responsible of autoxidation of theleukoaminochrome (96% of the total oxygen-de-

pendent autoxidation) [2, 24]. Therefore, the addi-tion of superoxide dismutase and catalase to theincubation mixture inhibited the formation of reac-tive oxygen species during the reduction of amino-chrome catalyzed by DT-diaphorase by preventingleukoaminochrome autoxidation. This antioxidantrole of superoxide dismutase and catalase on auto-xidation of leukoaminochrome during reduction of aminochrome catalyzed by DT-diaphorase con-trasts with their prooxidant role on leukoamino-chrome o-semiquinone autoxidation during amino-chrome reduction catalyzed by NADPH-cytochro-me P450 reductase [2]. These results support the

proposed protective role of DT-diaphorase in the presence of superoxide dismutase and catalaseagainst aminochrome-induced oxygen toxicity inthe neurodegenerative process of dopaminergicneuronal systems [2, 24]. It is interesting to note

the importance of reducing aminochrome to leu-koaminochrome, which can be conjugated by sul-fotransferase to an unreactive species, which canthen be excreted from the cell.

We have proposed neuroprotective role of DT-diaphorase [1, 2, 13, 15, 17, 23, 24, 26, 27], whichis supported by the following observations. Firstly,Cu-toxicity is dependent on DT-diaphorase inhibi-tion in RCSN-3 cells derived from the rat substan-tia nigra [17]. Indeed, uptake of CuSO

4

into RCSN-3cells does not induce toxicity per se, and Cu-uptake

increases 8-fold when the cells were incubated withCuSO

4

and dopamine. Cu in the complex Cu-dopa-mine catalyzed dopamine oxidation to aminochrome.However, the toxicity dramatically increased whenRCSN-3 cells were incubated with CuSO

4

, dopa-mine and dicoumarol, a specific inhibitor of DT-diaphorase. Secondly, the cytotoxic effect of MAO-Ainhibitor amiflamine in RCSN.3 cells increased2.4-fold (p < 0.001) in the presence of the inhibitor of DT-diaphorase, dicoumarol [13]. Thirdly, intra-cerebral administration of manganese (Mn 3 + ) to-gether with the DT-diaphorase inhibitor dicouma-rol into the left medial forebrain bundle produceda behavioral pattern characterized by contralateralrotational behavior when the rats were stimulatedwith apomorphine, in a manner similar to that ob-served in animals with unilateral 6-hydroxydopa-mine-induced lesions. The same animals rotated to-wards the opposite side, ipsilaterally, when stimu-lated with d-amphetamine. Thus, the finding thatthe concomitant application of Mn 3 + and inhibition

of DT-diaphorase by dicoumarol induces a 6-hy-droxydopamine-like behavior supports the idea thatDT-diaphorase may be a selective neuroprotectiveenzyme of the dopaminergic systems [23]. DT-diaphorase also plays a protective role in oxidativemetabolism of the endogenous dopamine-derivedneurotoxin, salsolinol. This compound was foundto decrease survival in the dopaminergic neuronalcell line RCSN-3, derived from the adult rat sub-stantia nigra, in a concentration-dependent manner.However, incubation of RCSN-3 cells with salsolinol

I S S N 1 2 3 0 - 6 0 0 2

577


OH + H2O

COMT

H2O 2

O 2

O 2

NAD(P)+NAD(P)H

.

NH

HO

HONH

O

O

NH

O

HO

NH

HO

CH3O

NH

HO

O

O2

.-

H2O2

.-O2

S

O

SOD

O O

H+

CAT,GSH-Px

Aminochrome

Leukoaminochrome o-semiquinone radical

Leukoaminochrome

DT-diaphorase

Sulfotransferase

Fig. 3.T w o - e l e c t r o n r e d u c t i o n o f a m i n o c h r o m e c a t a l y z e d b y D T - d i a p h o r a s e



in the presence of DT-diaphorase inhibitor signifi-cantly decreased cell survival by 2.5-fold (p < 0.001)[15].

CONCLUSIONS and DISCUSSION

The possible reactions involved in the oxida-tive-reductive pathways of dopamine have beenstudied, and our results strongly suggest that one-electron reduction of aminochrome is the reactionwhere the majority of reactive oxygen species isformed. Leukoaminochrome o-semiquinone is themost reactive species due to its reactivity with oxy-gen. The possible mechanisms underlying leuko-aminochrome o-semiquinone-induced damage inthe neurodegenerative process may include: (i) de-

pletion of NADH or NADPH; (ii) deactivation of enzymes by oxidizing thiol groups or essentialamino acids; (iii) deactivation of Ca-ATPase byoxidizing essential thiol groups; (iv) membranedamage by removal of a hydrogen from membranelipids, thus initiating lipid peroxidation, (v) forma-tion of superoxide radicals, hydrogen peroxide andhydroxyl radicals. The latter are potent radicals,which react with all biological molecules. There-fore, we postulate that the neurodegenerativeevents in dopaminergic systems depend on: (a) ex-cessive production of dopamine or low expression

of VMAT or MAO resulting in an increase in freedopamine, which autoxidizes to aminochrome; (b)inability of the cellular defenses to prevent the for-mation of leukoaminochrome o-semiquinone dueto (i) the existence of a polymorphism 609 (C ® T)expressing a non-enzymatically active DT-diapho-rase in Parkinson’s disease patients [28] (ii) lowlevel or lack of expression GST M1-1/M2-2.

Acknowledgment. This work was supported by FON-DECYT (N° 1020672).

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Received: September 19, 2002, in revised form: December 4, 2002.

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