153881-25-5Relevant articles and documents
Influence of glutathione on the oxidation chemistry of 5-S-cysteinyldopamine: Potentially neuroprotective reactions of relevance to Parkinson's disease
Shen, Xue-Ming,Dryhurst, Glenn
, p. 393 - 405 (2001)
In recent reports from this laboratory we have hypothesized that a key step underlying the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNc) in Parkinson's disease is an accelerated rate of oxidation of intraneuronal dopamine in the presence of L-cysteine (CySH) to form initially 5-S-cysteinyldopamine (5-S-CyS-DA). 5-S-CyS-DA, however, is more easily oxidized than dopamine in a reaction which leads to the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), a putative endogenously-formed metabolite that may be responsible for inhibition of mitochondrial complex I and α-ketoglutarate dehydrogenase, characteristic defects in the parkinsonian SNc. In this investigation it is demonstrated that glutathione (GSH) dramatically attenuates the oxidative transformation of 5-S-CyS-DA into DHBT-1 by two major pathways. In one pathway GSH displaces the cysteinyl residue from the o-quinone proximate oxidation product of 5-S-CyS-DA forming the corresponding glutathionyl conjugate that is attacked by GSH, to form 2,5-di-S-glutathionyldopamine, or by released CySH to give 2-S-cysteinyl-5-S-glutathionyldopamine. The former is the precursor of 2,5,6-tris-S-glutathionyldopamine, a major reaction product. However, intramolecular cyclization of the o-quinone proximate product of 2-S-cysteinyl-5-S-glutathionyldopamine is the first step in a pathway leading to glutathionyl conjugates of 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5). The second pathway involves nucleophilic addition of GSH to the o-quinone proximate oxidation product of 5-S-CyS-DA forming 2-S-glutathionyl-5-S-cysteinyldopamine the precursor of a number of glutathionyl conjugates of DHBT-1. These results raise the possibility that strategies which elevate intraneuronal levels of GSH in dopaminergic SNc cells in Parkinson's disease patients may block formation of the putative mitochondrial toxin DHBT-1 and hence be neuroprotective.
Effects of L-Cysteine on the Oxidation Chemistry of Dopamine: New Reaction Pathways of Potential Relevance to Idiopathic Parkinson's Disease
Zhang, Fa,Dryhurst, Glenn
, p. 1084 - 1098 (1994)
Oxidation of the catecholaminergic neurotransmitter dopamine (1) at physiological pH normally results in formation of black, insoluble melanin polymer.In this study, it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by scavenging the proximate o-quinone oxidation product of 1 to give 5-S-cysteinyldopamine (8).This cysteinyl conjugate is further oxidized in the presence of free CySH to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (11) and its 6-S-cysteinyl (12), 8-S-cysteinyl (14), and 6,8-di-S-cysteinyl (16)conjugates in addition to many other unidentified compounds. 5-S-Cysteinyldopamine (8) and dihydrobenzothiazines 11, 12, 14, and 16 are all more easily oxidized than 1.With increasing molar excesses of CySH, the formation of melanin is decreased and, ultimately, completely blocked.Preliminary experiments have revealed than when injected into the brains of laboratory mice, dihydrobenzothiazine 11 and its cysteinyl conjugates 12 and 14 are lethal and evoke profound behavioral responses including hyperactivity and tremor.On the basis of these results and other recent observations, a new hypothesis has been advanced which might help explain the selective degeneration of nigrostriatal dopaminergic neurons which occurs in idiopathic Parkinson's Disease (PD).This hypothesis proposes that in response to some form of chronic brain insult, the activity of γ-glutamyltranspeptidase is upregulated leading to an increased rate of translocation of glutathione (GSH) into the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN) pars compacta.The results of this in vitro study predict that such an elevated translocation of GSH intoheavily pigmented dopaminergic neurons would cause a diversion of the neuromelanin pathway with consequent depigmentation of these cells and formation of 8, all of which occur in the Parkinsonian SN.The further very facile oxidation of 8 which must occur under intraneuronal conditions where 1 is autoxidized, i.e., in neuromelanin-pigmented cells, would lead to dihydrobenzothiazine 11 and its cysteinyl conjugates which could be the endotoxins responsible for the selective degeneration of dopaminergic SN neurons in PD.The ease of autoxidation of 8 is suggested to account for the low levels of this conjugate found in the degenerating and Parkinsonian SN.The latter reaction and the intraneuronal autoxidation/redox cycling of 11 and its cysteinyl conjugates would be expected to result in greatly increased rates of intraneuronal formation of O2-radical anion which could (a) catalyze the oxidation of 1 by molecular oxygen, hence accounting for the significantly elevated 8/1 ratio observed in the Parkinsonian SN, and (b) lead to increased production of H2O2 and HO-radical, resulting in the extensive peroxidative damage which occurs in the SN in PD.
Oxidation of dopamine in the presence of cysteine: Characterization of new toxic products
Shen, Xue-Ming,Zhang, Fa,Dryhurst, Glenn
, p. 147 - 155 (2007/10/03)
Previous studies demonstrated that oxidation of dopamine (DA) in the presence of L-cysteine (CySH) at pH 7.4 gives a complex mixture of cysteinyl conjugates of the neurotransmitter that can be easily further oxidized to a number of dihydrobenzothiazines (DHBTs) along with unidentified yellow products. In this investigation, three of these products have been identified. 7-(2-Aminoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (BT-1) is formed as a result of oxidation of 5-S-cysteinyldopamine (5-S-CyS- DA) and 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3- carboxylic acid (DHBT-1). Regioisomers 6-(2-aminoethyl)1,8,9,10- tetrahydrobenzo[1,2-b:4,3-b']bis[1,4]thiazine-9-carboxylic acid (12) and 6- 2-aminoethyl)1,2,3,10-tetrahydrobenzo[1,2-b:4,3-b']bis[1,4]thiazine-2- carboxylic acid (13) are formed by oxidation of 2,5-bi-S-cysteinyldopamine (2,5-bi-S-CyS-DA), 6-S-cysteinyl-7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (DHBT-2), and 6-S-cysteinyl-8-(2- aminoethyl)-3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (DHBT-6). 2,5-Bi-S-CyS-DA, DHBT-2, and DHBT-6 are major early products of DA oxidation in the presence of CySH. However, because these three compounds are the most easily oxidized products formed in this reaction, they are subsequently transformed into 12 and 13, the latter regioisomer always being the major product. Both 12 (LD50 = 18.5 μg) and 13 (LD50 = 1.5 μg) are lethal when administered into the brains of mice and evoke hyperactivity and tremor. The potential relevance of the in vitro chemistry described in this and earlier reports to reactions that might occur in neuromelanin-pigmented dopaminergic neurons in Parkinson's disease is discussed.
