Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson's disease.
A very early event in the pathogenesis of idiopathic Parkinson's disease (PD) has been proposed to be an elevated translocation of L-cysteine (CySH) and/or glutathione (GSH) into pigmented dopaminergic cell bodies in the substantia nigra (SN) in which cytoplasmic dopamine (DA) is normally autoxidized to DA-o-quinone as the first step in a reaction leading to black neuromelanin polymer. Such an elevated influx of CySH and GSH would be expected to initially result in formation of 5-S-cysteinyldopamine (5-S-CyS-DA) and 5-S-glutathionyldopamine (5-S-Glu-DA), respectively, and might account for the massive irreversible loss of GSH and progressive depigmentation of SN cells that occurs in the Parkinsonian brain. However, 5-S-Glu-DA has not been detected in the Parkinsonian brain. Furthermore, although the 5-S-CyS-DA/DA and 5-S-CyS-DA/homovanillic acid concentration ratios increase significantly in the SN and cerebrospinal fluid, respectively, of PD patients, the absolute concentrations of 5-S-CyS-DA are extremely low and similar to those measured in age-matched control patients. One explanation for these observations is that 5-S-CyS-DA might be intraneuronally oxidized to more complex cysteinyldopamines and a number of dihydrobenzothiazines (DHBTs) and benzothiazines (BTs). Similarly, 5-S-Glu-DA might be intraneuronally oxidized to more complex glutathionyldopamines. In this investigation, however, it is demonstrated that 5-S-Glu-DA is rapidly metabolized in rat brain to 5-S-CyS-DA and 5-S-(N-acetylcysteinyl) dopamine (5) in reactions mediated by gamma-glutamyl transpeptidase (gamma-GT) and cysteine conjugate N-acetyltransferase. Similarly, 5-S-CyS-DA is metabolized to 5 in rat brain although more slowly than 5-S-Glu-DA. These reactions occur most rapidly in the midbrain, a region that contains the SN. Furthermore, 5, 2-S-(N-acetylcysteinyl)dopamine (6) and 2,5-di-S-(N-acetylcysteinyl)-dopamine (9) are toxic when administered into mouse brain having LD50 values of 14, 25, and 42 micrograms, respectively, and evoke a profound hyperactivity syndrome. These results suggest that the failure to detect 5-S-Glu-DA and the presence of only very low levels of 5-S-CyS-DA in Parkinsonian SN tissue and CSF might be related to both their intraneuronal oxidation and extraneuronal metabolism to N-acetylcysteinyl conjugates of DA. Furthermore, the toxic properties and neurobehavioral responses evoked by 5, 6, and 9 raise the possibility that these N-acetylcysteinyl conjugates of DA, in addition to certain cysteinyldopamines, DHBTs and BTs, might include endotoxins that contribute to SN cell death and other neuronal damage that occurs in PD. Methods are described for the synthesis of several N-acetylcysteinyl conjugates of DA, and their redox behaviors have been studied using cyclic voltammetry.
Shen
X M
XM
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
Xia
B
B
Wrona
M Z
MZ
Dryhurst
G
G
D000111:Acetylcysteine / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D003548:Cysteinyldopa / Q000096:biosynthesis* / Q000378:metabolism / Q000633:toxicity*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003548:Cysteinyldopa; D004298:Dopamine; D000111:Acetylcysteine