Oxidation of Dopamine in the Presence of Cysteine:  Characterization of New Toxic Products

Abstract

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.

Substrate specificity of human glutamine transaminase K as an aminotransferase and as a cysteine S-conjugate β-lyase

“…Many of these metabolites are neurotoxic by interfering with brain metabolism [53][54][55][56][57][58][59][60][61]. Strong evidence suggests that 5-S-L-cysteinyldopamine is an important precursor of the pheomelanin component of the pigment neuromelanin in the substantia nigra [54,[62][63][64]. Given the potential neurotoxicity of 5-S-L-cysteinyldopamine, incorporation into neuromelanin might be neuroprotective.…”

Dopamine Inactivates Tryptophan Hydroxylase and Forms a Redox-Cycling Quinoprotein: Possible Endogenous Toxin to Serotonin Neurons

“…C ellular defense mechanisms that might be expected to protect against oxidative stress (e.g., GSH or ascorbate) could actually contribute to redox cycling of a quinoprotein (Paz et al, 1991;Gieseg et al, 1993;Velez-Pardo et al, 1996). Quinoproteins could also have effects that are longer-lived than those of reactive oxygen species, DA, or DA-quinones in solution (Hastings et al, 1996a,b;Shen and Dryhurst, 1996;Shen et al, 1997). TPH represents the first identified target for DAquinone attack, and as a phenotypic marker for 5-HT neurons, it would be in a position to have detrimental cellular effects in vivo via its redox-cycling properties.…”

The Parkinsonism-inducing Drug 1-Methyl-4-phenylpyridinium Triggers Intracellular Dopamine Oxidation

“…69). These products might be expected to generate a variety of aberrant oxidative metabolites of DA including 6-hydroxydopamine (70), 5-S-cysteinyl-DA (29,31), and other more complex dihydrobenzothiazines (71,72). Several of these compounds can also inhibit Complex I, further affecting energy impairment (67).…”