Oxidation of dopamine in the presence of cysteine: characterization of new toxic products.
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 Aimoethyl)-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-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-2H-1,4-benzothiazine-3-carboxy lic 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 micrograms) and 13 (LD50 = 1.5 microgram) 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 reaction that might occur in neuromelanin-pigmented dopaminergic neurons in Parkinson's disease is discussed.
Shen
X M
XM
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
Zhang
F
F
Dryhurst
G
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology*; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction / Q000187:drug effects
D003545:Cysteine; D004298:Dopamine