- Email: [email protected]
The oxidative metabolism of catecholamines in the brain: a review
Biochimica et Biophysica Acta 1380 Ž1998. 159–162
Review
The oxidative metabolism of catecholamines in the brain: a review John Smythies a
a,)
, Lauro Galzigna
b
Institute of Neurology, Queen Square, London WC1 3BG, UK and Brain and Perception Laboratory, Center for Human Information Processing, U.C.S.D., La Jolla, CA 92093-0109, USA b Department of Biochemistry, UniÕersity of Padua, Via Trieste 75, Padua, Italy Received 31 July 1997; revised 24 September 1997; accepted 3 October 1997
Abstract This paper summarizes the strong evidence that we now have that the oxidative pathway of metabolism of the catecholamines, dopamine and norepinephrine via their respective quinones occurs in vivo in the brain. This fact is not yet widely appreciated. The evidence is based on the chemical structure of neuromelanin, advanced mass spectrometry techniques and the identification of intermediates of this system, such as 5-cysteinyl dopamine, in the brain. Supportive evidence is presented from a number of sources including enzymology. A suggestion as to the possible normal function of this system is made. q 1998 Elsevier Science B.V. Keywords: Aminochrome; Neuromelanin; Catecholamine auto-oxidation
In current Textbooks of Biochemistry only two pathways for the metabolism of catecholamines in the human are described – the one by monoamine oxidase w1x and the second by catecholamine O-methyl transferase w2x. It has been known for over a century that catecholamines will auto-oxidize in solution to form coloured pigments which then polymerize to form black, insoluble melanins Ž for a general review see w3x.. The complex organic chemistry of these reactions has been partially described w4–7x. One experiment that carried much weight at that time was carried out by Schayer and Smiley w8x who reported that the administration of 14C-labelled adrenaline does not give rise to the endogenous formation of 14Clabelled adrenochrome. Unfortunately they did not repeat the experiment with either dopamine or nor-
)
Corresponding author. Fax: q1 619 534 7190; E-mail: [email protected]
adrenaline, and, in any case the animal used was inappropriate, namely the rat, which does not form neuromelanin. In addition, adrenochrome is an extremely short-lived intermediate and under normal conditions is very quickly metabolized thus disappearing from the tissues. So, until recently, it was the general opinion that the auto-oxidative pathway was followed only in vitro not in vivo. In other words it was relevant to organic chemistry not to biochemistry. However, it is now apparent that this view is mistaken. The next development occurred in 1965 when Goodwin et al. w9x found that neuromelanin is a polymer made up of units of 5,6,-dihydroxyindole, which is a metabolite of dopamine along the autooxidative pathway. In this pathway dopamine forms first dopamine quinone Ž Fig. 1Žb.. . This reaction may be non-enzymatic or it may be accelerated by various oxidases and peroxidases, and is reversible by an antioxidant such as ascorbate or glutathione. Then
0304-4165r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 4 - 4 1 6 5 Ž 9 7 . 0 0 1 3 1 - 1
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J. Smythies, L. Galzignar Biochimica et Biophysica Acta 1380 (1998) 159–162
Fig. 1. Ža. dopamine, Žb. dopamine quinone, Žc. dopaminochrome Ža.k.a. aminochrome: this may also be depicted as the zwitterion., Žd. dopamine o-semiquinone, Že. dopamine o-hydroquinone, Žf. 5,6- dihydroxy indole.
dopamine quinone cyclizes irreversibly and spontaneously to form dopaminochrome Žalso called aminochrome. ŽFig. 1Ž c... This in turn forms 5,6-dihydroxyindole ŽFig. 1Žf... Further details of this metabolic pathway will be given later. However, the implication of Goodwin et al.’s findings – that dopaminochrome, as the necessary precursor of neuromelanin, must occur in the brain – was never implicitly made. In fact eleven years later Tse et al. w10x reviewed the field and stated that although the oxidation of catecholamines in vitro was well established the existence of this pathway in vivo ‘‘...is still open to question’’. However, they went on to say that, if such oxidized products could occur even at picogram quantities this could have ‘‘...serious functional significance’’. So the subject continued to slumber for the next twenty years until Matthews et al. w11x reported that polymorphonuclear leucocytes metabolize 80% of the ambient adrenaline via the adrenochrome pathway, presumably, since adrenochrome is highly cytotoxic, as part of the armamentarium the leucocyte uses to kill bacteria. Again this solitary report was never repeated or developed, although recently the role of inflammatory processes in the brain Žmediated in part by microglia. and oxida-
tive stress have been implicated in the genesis of Alzheimers disease. Two years later Fornstedt et al. w12x from Arvid Carlsson’s laboratory in Goteborg found that 5¨ cysteinyldopamine – a metabolite of dopamine quinone – occurs in human brain tissue. So presumably dopamine quinone must occur too. Then Carstam et al. w13x reported that 5-cysteinyldopamine is itself metabolized to benzothiazoles which are incorporated into neuromelanin. These benzothiazoles are highly neurotoxic and have been implicated in the genesis of Parkinson’s disease w14x. Finally Costa et al. w15x provided the final evidence that dopaminochrome occurs in brain Žas well as its o-semiquinone ŽFig. 1Žd.. and o-hydroquinone Ž Fig. 1Že.. derivatives., by definitive Eli and FAA mass spectrometry plus collisional analysis. So, if these compounds occur in brain, where do they come from and what is their physiological significance, if any? Several oxidases will convert dopamine in vitro to dopamine quinones w3,16–19x but what is needed is a demonstration of a mechanism that actually operates in vivo. In 1995 it was independently reported w20,21x that the inducible enzyme prostaglandin H synthase Ž a.k.a. cyclo-oxygenase. Žwhich is the rate-limiting step in prostaglandin synthesis. in striatal in vitro preparations, during the conversion of arachidonic acid to prostaglandin H, will use as a co-factor dopamine which is co-oxidized to dopaminochrome. This enzyme is normally activated by phospholipase A2mediated arachidonic acid release, which in turn, at the glutamate synapse, is activated by the Ca2q cascade. However, no evidence has as yet been presented that this reaction occurs in vivo. Much in vitro evidence has also accumulated that the neurotoxic effects of dopamine on neurons in tissue culture are mediated by dopamine quinones w22–24x acting, not on dopamine receptors but on NMDA glutamate receptors w25x. A major target of these dopamine quinones has been identified as the mitochondrial electron transport system and activation of proteases and lipases w24x. They are also potent irreversible inhibitors of COMT w26x which may be significant because this enzyme plays a role against dopamine o-semiquinone toxicity Ž see below. . But again we do not know if any of this is true in vivo.
J. Smythies, L. Galzignar Biochimica et Biophysica Acta 1380 (1998) 159–162
Neuromelanin is formed as granules in the cytoplasm of dopaminergic neurons in the substantia nigra and ventral tegmental area and in noradrenergic neurons in the locus coeruleus w27x. As far as is known it does not occur in the adrenergic A1-3 neurons in the brainstem, so there is currently no evidence that adrenochrome itself occurs in brain. Neuromelanin is not found at birth but then slowly but steadily accumulates until old age. So this presumably represents one site of formation of catecholamine quinones. Neuromelanin is a powerful chelator of heavy metals, including iron, the redox properties of which reaction is thought to play a role in the genesis of Parkinson’s disease. But another site is possible. In the cerebral cortex dopamine terminals are mainly in the form of non-synaptic boutons-enpassage of which many are attached to the side of glutamatergic synapses on dendritic spines, such that dopamine released could ‘‘spill over’’ into the glutamate synapse only 1–2 m away w28x. As has been described in detail elsewhere w29,30x the glutamate synapse contains a complex redox mechanism that may control the growth or deletion of that synapse. One factor in this complex mechanism, in a low anti-oxidant environment, is the potential oxidation of dopamine to dopamine o-semiquinone by reactive nitrogen species derived from nitric oxide w31x. Dopamine o-semiquinone is a highly toxic free radical molecule and could play a role in spine pruning. Further indirect evidence that dopamine quinones occur in brain is provided by the work of Segura– Aguilar w19x who has described a complex enzyme chain in brain tissue that is involved in their metabolism ŽFig. 2.. Dopaminochrome may be metabolized by either of two enzymes Ž a. DT-diaphorase to form the o-hydroquinone which is metabolized by COMT or sulphotransferase to form inactive products that are excreted in the urine. 5,6dihydroxyindole is also O-methylated by COMT Žat position 6. and by hydroxyindole O-methyl transferase Žat position 5. w32x to products also found in urine. The second route Ž b. is by NAHPD-cytochrome P450 reductase to the o-semiquinone. The auto-oxidation of the Žneuroprotective. o-hydroquinone to the Ž neurotoxic. o-semiquinone is normally prevented by the antioxidant enzymes superoxide dismutase and catalase. The possible role of DT-diaphorase in preventing the formation of toxic
161
Fig. 2. A diagram of the dopamine auto-oxidation pathway. AA arachidonic acid; C ascorbic acid; GSH glutathione; NM neuromelanin; NMDA R N-methyl-D-aspartate glutamate receptor; PG Hs prostaglandin H synthase; ROS reactive oxygen species; SOD superoxide dismutase Žshown inhibiting the conversion of the o-hydroquinone to the o-semiquinone.; ST sulphotransferase.
catecholamine o-semiquinones has also been suggested by Bindoli et al. w33x. It seems logical to suppose that if DT-diaphorase and NAHPD-cytochrome P450 are present in brain tissue then their substrates are likely to be present also. There is thus now conclusive evidence Ž from the report by Costa et al. w15x, the chemistry of neuromelanin and the occurrence of 5-cysteinyl dopamine in brain. that the oxidative pathway of catecholamine metabolism occurs in the brain in vivo, at least in the case of dopamine and norepinephrine.
References w1x R.W. Schayer, R.L. Smiley, E.H. Kaplan, The metabolism of epinephrine containing isotopic carbon II, J. Biol. Chem. 198 Ž1952. 545–551. w2x J. Axelrod, O-methylation of epinephrine and other catechols in vitro and in vivo, Science 126 Ž1957. 400–401. w3x A. Bindoli, M.P. Rigobello, L. Galzigna, Toxicology of aminochromes, Toxicol. Lett. 48 Ž1989. 3–20. w4x D.E. Green, D. Richter, Adrenaline and adrenochrome, Biochem. J. 31 Ž1937. 596–616. w5x J. Harley-Mason, The structure of adrenochrome and related products, Experientia 4 Ž1948. 307–311. w6x R.A. Heacock, W.S. Powell, Adrenochrome and related compounds, Prog. Med. Chem. 9 Ž1973. 276–339. w7x D.G. Graham, On the origin and significance of neuromelanin, Arch. Pathol. Lab. Med. 103 Ž1979. 359–362.
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w8x R.W. Schayer, R.L. Smiley, The metabolism of epinephrine containing isotopic carbon III, J. Biol. Chem. 202 Ž1953. 425–430. w9x F. Goodwin, D. Shafritz, H. Weissbach, In vitro polypeptide synthesis in brain, Arch. Biochem. Biophys. 130 Ž1965. 183–190. w10x D.C.S. Tse, R.L. McCreery, R.N. Adams, Potential oxidative pathways of brain catecholamines, J. Med. Chem. 19 Ž1976. 37–40. w11x S.B. Matthews, A.H. Henderson, A.K. Campbell, The adrenochrome pathway: the major route for adrenalin catabolism by polymorphnuclear leucocytes, J. Mol. Cell. Cardiol. 17 Ž1985. 339–348. w12x B. Fornstedt, A. Brun, E. Rosengren, A. Carlsson, The apparent autoxidation rate of catechols in dopamine-rich regions of human brains increases with the degree of depigmentation of substantia nigra, J. Neural Trans. I Ž1989. 279–295. w13x R. Carstam, C. Brinck, Hindemith Augustsson, H. Rohsman, E. Rosengren, The neuromelanin of the human substantia nigra, Biochim. Biophys. Acta 1097 Ž1991. 152–160. w14x F. Zhang, G. Dryhurst, Effects of L-cysteine on the oxidative chemistry of dpamine: new reaction pathways of potential relevance to ideopathic Parkinson’s disease, J. Med. Chem. 37 Ž1994. 1084–1096. w15x C. Costa, A. Bertazzo, G. Allegri et al., Melanin biosynthesis from dopamine. II. A mass spectrometric and collisional spectroscopic investigation, Pigment Cell Res. 5 Ž1992. 122–131. w16x J. Axelrod, Enzymatic oxidation of epinephrine to adrenochrome by the salivary gland, Biochim. Biophys. Acta 85 Ž1964. 247–254. w17x M.B. Grisham, V.J. Perez, J. Everse, Neuromelanogneic and cytotoxic properties of canine brain stem peroxidase, J. Neurochem. 48 Ž1987. 876–882. w18x H.M. Schipper, Y. Kotake, E.G. Janzen, Catechol oxidation by peroxidase-positive astrocytes in primary culture: an electron spin resonance study, J. Neurosci. 11 Ž1991. 2170– 2176. w19x J. Segura-Aguilar, Peroxidase activity of liver microsomal vitamin D 25-hydroxylase and cytochrome P450 1A2 catalyzes 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome, Biochem. Mol. Med. 58 Ž1996. 122–129.
w20x T.G. Hastings, Enzymatic oxidation of dopamine: the role of prostaglandin H synthase, J. Neurochem. 64 Ž1995. 919–924. w21x M.B. Mattammal, R. Strong, V.M. Lakshmi et al., Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson’s disease, J. Neurochem. 64 Ž1995. 1645–1654. w22x P.P. Michel, F. Hefti, Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture, J. Neurosci. Res. 76 Ž1990. 428–435. w23x J. Cadet L, L.A. Kahler, Free radical mechanisms in schizophrenia and tardive dyskinesia, Neurosci. Biobehav. Rev. 18 Ž1994. 457–467. w24x D. Ben-Shacher, B. Zuk, Y. Glinka, Dopamine neurotoxicity: inhibition of mitochondrial respiration, J. Neurochem. 64 Ž1995. 718–723. w25x K. Lieb, J. Andrae, I. Reisert et al., Neurotoxicity of dopamine and protective effects of the NMDA receptor antagonist AP-5 differ between male and female neurons, Exp. Neurol. 134 Ž1995. 222–229. w26x R.T. Borchardt, Affinity labelling of catecholamine 0-methyltransferase by the oxidation products of 6-hydroxy dopamine, Mol. Pharmacol. 11 Ž1975. 436–449. w27x J.R. Smythies, On the function of neuromelanin, Proc. R. Soc. London, Ser. B 263 Ž1996. 491–496. w28x R. Kotter, Postsynaptic integration of glutamatergic and ¨ dopaminergic signals in the striatum, Prog. Neurobiol. 44 Ž1994. 163–196. w29x J.R. Smythies, Oxidative reactions and schizophrenia, Schizophr. Res. 24 Ž1997. 357–364. w30x J.R. Smythies, The biochemical basis of synaptic plasticity and neural computation: a new theory, Proc. R. Soc. London, Ser. B 264 Ž1997. 575–579. w31x J.A. Cook, D.A. Wink, V. Blount et al., Role of antioxidants in the nitric oxide-elicited inhibition of dopamine uptake in cultured mesencephalic neurons. Insights into potential mechanisms of nitric oxide-mediated neurotoxicity, Neurochem. Int. 28 Ž1996. 609–617. w32x J. Axelrod, A.B. Lerner, O-methylation in the conversion of tyrosine to melanin, Biochim. Biophys. Acta 71 Ž1963. 650–655. w33x A. Bindoli, M.P. Rigobello, L. Galzigna, Reduction of adrenochrome by rat liver and brain DT-diaphorase, Free Radic. Res. Comms. 8 Ž1990. 295–298.
Review
The oxidative metabolism of catecholamines in the brain: a review John Smythies a
a,)
, Lauro Galzigna
b
Institute of Neurology, Queen Square, London WC1 3BG, UK and Brain and Perception Laboratory, Center for Human Information Processing, U.C.S.D., La Jolla, CA 92093-0109, USA b Department of Biochemistry, UniÕersity of Padua, Via Trieste 75, Padua, Italy Received 31 July 1997; revised 24 September 1997; accepted 3 October 1997
Abstract This paper summarizes the strong evidence that we now have that the oxidative pathway of metabolism of the catecholamines, dopamine and norepinephrine via their respective quinones occurs in vivo in the brain. This fact is not yet widely appreciated. The evidence is based on the chemical structure of neuromelanin, advanced mass spectrometry techniques and the identification of intermediates of this system, such as 5-cysteinyl dopamine, in the brain. Supportive evidence is presented from a number of sources including enzymology. A suggestion as to the possible normal function of this system is made. q 1998 Elsevier Science B.V. Keywords: Aminochrome; Neuromelanin; Catecholamine auto-oxidation
In current Textbooks of Biochemistry only two pathways for the metabolism of catecholamines in the human are described – the one by monoamine oxidase w1x and the second by catecholamine O-methyl transferase w2x. It has been known for over a century that catecholamines will auto-oxidize in solution to form coloured pigments which then polymerize to form black, insoluble melanins Ž for a general review see w3x.. The complex organic chemistry of these reactions has been partially described w4–7x. One experiment that carried much weight at that time was carried out by Schayer and Smiley w8x who reported that the administration of 14C-labelled adrenaline does not give rise to the endogenous formation of 14Clabelled adrenochrome. Unfortunately they did not repeat the experiment with either dopamine or nor-
)
Corresponding author. Fax: q1 619 534 7190; E-mail: [email protected]
adrenaline, and, in any case the animal used was inappropriate, namely the rat, which does not form neuromelanin. In addition, adrenochrome is an extremely short-lived intermediate and under normal conditions is very quickly metabolized thus disappearing from the tissues. So, until recently, it was the general opinion that the auto-oxidative pathway was followed only in vitro not in vivo. In other words it was relevant to organic chemistry not to biochemistry. However, it is now apparent that this view is mistaken. The next development occurred in 1965 when Goodwin et al. w9x found that neuromelanin is a polymer made up of units of 5,6,-dihydroxyindole, which is a metabolite of dopamine along the autooxidative pathway. In this pathway dopamine forms first dopamine quinone Ž Fig. 1Žb.. . This reaction may be non-enzymatic or it may be accelerated by various oxidases and peroxidases, and is reversible by an antioxidant such as ascorbate or glutathione. Then
0304-4165r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 4 - 4 1 6 5 Ž 9 7 . 0 0 1 3 1 - 1
160
J. Smythies, L. Galzignar Biochimica et Biophysica Acta 1380 (1998) 159–162
Fig. 1. Ža. dopamine, Žb. dopamine quinone, Žc. dopaminochrome Ža.k.a. aminochrome: this may also be depicted as the zwitterion., Žd. dopamine o-semiquinone, Že. dopamine o-hydroquinone, Žf. 5,6- dihydroxy indole.
dopamine quinone cyclizes irreversibly and spontaneously to form dopaminochrome Žalso called aminochrome. ŽFig. 1Ž c... This in turn forms 5,6-dihydroxyindole ŽFig. 1Žf... Further details of this metabolic pathway will be given later. However, the implication of Goodwin et al.’s findings – that dopaminochrome, as the necessary precursor of neuromelanin, must occur in the brain – was never implicitly made. In fact eleven years later Tse et al. w10x reviewed the field and stated that although the oxidation of catecholamines in vitro was well established the existence of this pathway in vivo ‘‘...is still open to question’’. However, they went on to say that, if such oxidized products could occur even at picogram quantities this could have ‘‘...serious functional significance’’. So the subject continued to slumber for the next twenty years until Matthews et al. w11x reported that polymorphonuclear leucocytes metabolize 80% of the ambient adrenaline via the adrenochrome pathway, presumably, since adrenochrome is highly cytotoxic, as part of the armamentarium the leucocyte uses to kill bacteria. Again this solitary report was never repeated or developed, although recently the role of inflammatory processes in the brain Žmediated in part by microglia. and oxida-
tive stress have been implicated in the genesis of Alzheimers disease. Two years later Fornstedt et al. w12x from Arvid Carlsson’s laboratory in Goteborg found that 5¨ cysteinyldopamine – a metabolite of dopamine quinone – occurs in human brain tissue. So presumably dopamine quinone must occur too. Then Carstam et al. w13x reported that 5-cysteinyldopamine is itself metabolized to benzothiazoles which are incorporated into neuromelanin. These benzothiazoles are highly neurotoxic and have been implicated in the genesis of Parkinson’s disease w14x. Finally Costa et al. w15x provided the final evidence that dopaminochrome occurs in brain Žas well as its o-semiquinone ŽFig. 1Žd.. and o-hydroquinone Ž Fig. 1Že.. derivatives., by definitive Eli and FAA mass spectrometry plus collisional analysis. So, if these compounds occur in brain, where do they come from and what is their physiological significance, if any? Several oxidases will convert dopamine in vitro to dopamine quinones w3,16–19x but what is needed is a demonstration of a mechanism that actually operates in vivo. In 1995 it was independently reported w20,21x that the inducible enzyme prostaglandin H synthase Ž a.k.a. cyclo-oxygenase. Žwhich is the rate-limiting step in prostaglandin synthesis. in striatal in vitro preparations, during the conversion of arachidonic acid to prostaglandin H, will use as a co-factor dopamine which is co-oxidized to dopaminochrome. This enzyme is normally activated by phospholipase A2mediated arachidonic acid release, which in turn, at the glutamate synapse, is activated by the Ca2q cascade. However, no evidence has as yet been presented that this reaction occurs in vivo. Much in vitro evidence has also accumulated that the neurotoxic effects of dopamine on neurons in tissue culture are mediated by dopamine quinones w22–24x acting, not on dopamine receptors but on NMDA glutamate receptors w25x. A major target of these dopamine quinones has been identified as the mitochondrial electron transport system and activation of proteases and lipases w24x. They are also potent irreversible inhibitors of COMT w26x which may be significant because this enzyme plays a role against dopamine o-semiquinone toxicity Ž see below. . But again we do not know if any of this is true in vivo.
J. Smythies, L. Galzignar Biochimica et Biophysica Acta 1380 (1998) 159–162
Neuromelanin is formed as granules in the cytoplasm of dopaminergic neurons in the substantia nigra and ventral tegmental area and in noradrenergic neurons in the locus coeruleus w27x. As far as is known it does not occur in the adrenergic A1-3 neurons in the brainstem, so there is currently no evidence that adrenochrome itself occurs in brain. Neuromelanin is not found at birth but then slowly but steadily accumulates until old age. So this presumably represents one site of formation of catecholamine quinones. Neuromelanin is a powerful chelator of heavy metals, including iron, the redox properties of which reaction is thought to play a role in the genesis of Parkinson’s disease. But another site is possible. In the cerebral cortex dopamine terminals are mainly in the form of non-synaptic boutons-enpassage of which many are attached to the side of glutamatergic synapses on dendritic spines, such that dopamine released could ‘‘spill over’’ into the glutamate synapse only 1–2 m away w28x. As has been described in detail elsewhere w29,30x the glutamate synapse contains a complex redox mechanism that may control the growth or deletion of that synapse. One factor in this complex mechanism, in a low anti-oxidant environment, is the potential oxidation of dopamine to dopamine o-semiquinone by reactive nitrogen species derived from nitric oxide w31x. Dopamine o-semiquinone is a highly toxic free radical molecule and could play a role in spine pruning. Further indirect evidence that dopamine quinones occur in brain is provided by the work of Segura– Aguilar w19x who has described a complex enzyme chain in brain tissue that is involved in their metabolism ŽFig. 2.. Dopaminochrome may be metabolized by either of two enzymes Ž a. DT-diaphorase to form the o-hydroquinone which is metabolized by COMT or sulphotransferase to form inactive products that are excreted in the urine. 5,6dihydroxyindole is also O-methylated by COMT Žat position 6. and by hydroxyindole O-methyl transferase Žat position 5. w32x to products also found in urine. The second route Ž b. is by NAHPD-cytochrome P450 reductase to the o-semiquinone. The auto-oxidation of the Žneuroprotective. o-hydroquinone to the Ž neurotoxic. o-semiquinone is normally prevented by the antioxidant enzymes superoxide dismutase and catalase. The possible role of DT-diaphorase in preventing the formation of toxic
161
Fig. 2. A diagram of the dopamine auto-oxidation pathway. AA arachidonic acid; C ascorbic acid; GSH glutathione; NM neuromelanin; NMDA R N-methyl-D-aspartate glutamate receptor; PG Hs prostaglandin H synthase; ROS reactive oxygen species; SOD superoxide dismutase Žshown inhibiting the conversion of the o-hydroquinone to the o-semiquinone.; ST sulphotransferase.
catecholamine o-semiquinones has also been suggested by Bindoli et al. w33x. It seems logical to suppose that if DT-diaphorase and NAHPD-cytochrome P450 are present in brain tissue then their substrates are likely to be present also. There is thus now conclusive evidence Ž from the report by Costa et al. w15x, the chemistry of neuromelanin and the occurrence of 5-cysteinyl dopamine in brain. that the oxidative pathway of catecholamine metabolism occurs in the brain in vivo, at least in the case of dopamine and norepinephrine.
References w1x R.W. Schayer, R.L. Smiley, E.H. Kaplan, The metabolism of epinephrine containing isotopic carbon II, J. Biol. Chem. 198 Ž1952. 545–551. w2x J. Axelrod, O-methylation of epinephrine and other catechols in vitro and in vivo, Science 126 Ž1957. 400–401. w3x A. Bindoli, M.P. Rigobello, L. Galzigna, Toxicology of aminochromes, Toxicol. Lett. 48 Ž1989. 3–20. w4x D.E. Green, D. Richter, Adrenaline and adrenochrome, Biochem. J. 31 Ž1937. 596–616. w5x J. Harley-Mason, The structure of adrenochrome and related products, Experientia 4 Ž1948. 307–311. w6x R.A. Heacock, W.S. Powell, Adrenochrome and related compounds, Prog. Med. Chem. 9 Ž1973. 276–339. w7x D.G. Graham, On the origin and significance of neuromelanin, Arch. Pathol. Lab. Med. 103 Ž1979. 359–362.
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J. Smythies, L. Galzignar Biochimica et Biophysica Acta 1380 (1998) 159–162
w8x R.W. Schayer, R.L. Smiley, The metabolism of epinephrine containing isotopic carbon III, J. Biol. Chem. 202 Ž1953. 425–430. w9x F. Goodwin, D. Shafritz, H. Weissbach, In vitro polypeptide synthesis in brain, Arch. Biochem. Biophys. 130 Ž1965. 183–190. w10x D.C.S. Tse, R.L. McCreery, R.N. Adams, Potential oxidative pathways of brain catecholamines, J. Med. Chem. 19 Ž1976. 37–40. w11x S.B. Matthews, A.H. Henderson, A.K. Campbell, The adrenochrome pathway: the major route for adrenalin catabolism by polymorphnuclear leucocytes, J. Mol. Cell. Cardiol. 17 Ž1985. 339–348. w12x B. Fornstedt, A. Brun, E. Rosengren, A. Carlsson, The apparent autoxidation rate of catechols in dopamine-rich regions of human brains increases with the degree of depigmentation of substantia nigra, J. Neural Trans. I Ž1989. 279–295. w13x R. Carstam, C. Brinck, Hindemith Augustsson, H. Rohsman, E. Rosengren, The neuromelanin of the human substantia nigra, Biochim. Biophys. Acta 1097 Ž1991. 152–160. w14x F. Zhang, G. Dryhurst, Effects of L-cysteine on the oxidative chemistry of dpamine: new reaction pathways of potential relevance to ideopathic Parkinson’s disease, J. Med. Chem. 37 Ž1994. 1084–1096. w15x C. Costa, A. Bertazzo, G. Allegri et al., Melanin biosynthesis from dopamine. II. A mass spectrometric and collisional spectroscopic investigation, Pigment Cell Res. 5 Ž1992. 122–131. w16x J. Axelrod, Enzymatic oxidation of epinephrine to adrenochrome by the salivary gland, Biochim. Biophys. Acta 85 Ž1964. 247–254. w17x M.B. Grisham, V.J. Perez, J. Everse, Neuromelanogneic and cytotoxic properties of canine brain stem peroxidase, J. Neurochem. 48 Ž1987. 876–882. w18x H.M. Schipper, Y. Kotake, E.G. Janzen, Catechol oxidation by peroxidase-positive astrocytes in primary culture: an electron spin resonance study, J. Neurosci. 11 Ž1991. 2170– 2176. w19x J. Segura-Aguilar, Peroxidase activity of liver microsomal vitamin D 25-hydroxylase and cytochrome P450 1A2 catalyzes 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome, Biochem. Mol. Med. 58 Ž1996. 122–129.
w20x T.G. Hastings, Enzymatic oxidation of dopamine: the role of prostaglandin H synthase, J. Neurochem. 64 Ž1995. 919–924. w21x M.B. Mattammal, R. Strong, V.M. Lakshmi et al., Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson’s disease, J. Neurochem. 64 Ž1995. 1645–1654. w22x P.P. Michel, F. Hefti, Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture, J. Neurosci. Res. 76 Ž1990. 428–435. w23x J. Cadet L, L.A. Kahler, Free radical mechanisms in schizophrenia and tardive dyskinesia, Neurosci. Biobehav. Rev. 18 Ž1994. 457–467. w24x D. Ben-Shacher, B. Zuk, Y. Glinka, Dopamine neurotoxicity: inhibition of mitochondrial respiration, J. Neurochem. 64 Ž1995. 718–723. w25x K. Lieb, J. Andrae, I. Reisert et al., Neurotoxicity of dopamine and protective effects of the NMDA receptor antagonist AP-5 differ between male and female neurons, Exp. Neurol. 134 Ž1995. 222–229. w26x R.T. Borchardt, Affinity labelling of catecholamine 0-methyltransferase by the oxidation products of 6-hydroxy dopamine, Mol. Pharmacol. 11 Ž1975. 436–449. w27x J.R. Smythies, On the function of neuromelanin, Proc. R. Soc. London, Ser. B 263 Ž1996. 491–496. w28x R. Kotter, Postsynaptic integration of glutamatergic and ¨ dopaminergic signals in the striatum, Prog. Neurobiol. 44 Ž1994. 163–196. w29x J.R. Smythies, Oxidative reactions and schizophrenia, Schizophr. Res. 24 Ž1997. 357–364. w30x J.R. Smythies, The biochemical basis of synaptic plasticity and neural computation: a new theory, Proc. R. Soc. London, Ser. B 264 Ž1997. 575–579. w31x J.A. Cook, D.A. Wink, V. Blount et al., Role of antioxidants in the nitric oxide-elicited inhibition of dopamine uptake in cultured mesencephalic neurons. Insights into potential mechanisms of nitric oxide-mediated neurotoxicity, Neurochem. Int. 28 Ž1996. 609–617. w32x J. Axelrod, A.B. Lerner, O-methylation in the conversion of tyrosine to melanin, Biochim. Biophys. Acta 71 Ž1963. 650–655. w33x A. Bindoli, M.P. Rigobello, L. Galzigna, Reduction of adrenochrome by rat liver and brain DT-diaphorase, Free Radic. Res. Comms. 8 Ž1990. 295–298.