OXIDATION OF DOPAMINE IN THE PRESENCE OF CYSTEINE - CHARACTERIZATION OF NEW TOXIC PRODUCTS

Previous studies demonstrated that oxidation of dopamine (DA) in the p resence of L-cysteine (CySH) at pH 7.4 gives a complex mixture of cyst einyl conjugates of the neurotransmitter that can be easily further ox idized to a number of dihydrobenzothiazines (DHBTs) along with unident ified yellow products. In this investigation, three of these products have been identified. inoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxyl ic acid (BT-1) is formed as a result of oxidation of 5-S-cysteinyldopa mine (5-S-CyS-DA) and hyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine- 3- -carboxylic acid (DHBT-1). Regioisomers robenzo[1,2-b:4,3-b']bis[1, 4]thiazine-9-carboxylic acid(12) and robenzo[1,2-b:4,3-b']bis[1,4]thia zine-2-carboxylic acid (13) are formed by oxidation of 2,5-bi-S-cystei nyldopamine (2,5-bi-S-CyS-DA), hydro-5-hydroxy-2H-1,4-benz-othiazine-3 -carboxylic acid (DHBT-2), and ihydro-5-hydroxy-2H-1,4-benzothiazine-3 -carboxylic acid (DHBT-6). 2,5-Bi-S-CyS-DA, DHBT-2, and DHBT-6 are maj or early products of DA oxidation in the presence of CySH. However, be cause these three compounds are the most easily oxidized products form ed in this reaction, they are subsequently transformed into 12 and 13, the latter regioisomer always being the major product. Both 12 (LD(50 ) = 18.5 mu g) and 13 (LD(50) = 1.5 mu g) are lethal when administered into the brains of mice and evoke hyperactivity and tremor. The poten tial relevance of the in vitro chemistry described in this and earlier reports to reactions that might occur in neuromelanin-pigmented dopam inergic neurons in Parkinson's disease is discussed.