Shen X M, Zhang F, Dryhurst G
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
Chem Res Toxicol. 1997 Feb;10(2):147-55. doi: 10.1021/tx960145c.
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.
先前的研究表明，在pH 7.4条件下，多巴胺（DA）在L-半胱氨酸（CySH）存在时发生氧化，会生成神经递质的半胱氨酰共轭物的复杂混合物，这些共轭物很容易进一步氧化为多种二氢苯并噻嗪（DHBTs）以及不明黄色产物。在本研究中，已鉴定出其中三种产物。7-(2-氨基乙基)-5-羟基-1,4-苯并噻嗪-3-羧酸（BT-1）是由5-S-半胱氨酰多巴胺（5-S-CyS-DA）和7-(2-氨基乙基)-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸（DHBT-1）氧化形成的。区域异构体6-(2-氨基乙基)-1,8,9,10-四氢苯并[1,2-b:4,3-b']双[1,4]噻嗪-9-羧酸（12）和6-(2-氨基乙基)-1,2,3,10-四氢苯并[1,2-b:4,3-b']双[1,4]噻嗪-2-羧酸（13）是由2,5-双-S-CyS-DA、6-S-半胱氨酰-7-(2-氨基乙基)-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸（DHBT-2）和6-S-半胱氨酰-8-(2-氨基乙基)-3,4-二氢-2H-1,4-苯并噻嗪-3-羧酸（DHBT-6）氧化形成的。2,5-双-S-CyS-DA、DHBT-2和DHBT-6是DA在CySH存在下氧化的主要早期产物。然而，由于这三种化合物是该反应中最易氧化的产物，它们随后会转化为12和13，后一种区域异构体始终是主要产物。12（半数致死量=18.5微克）和13（半数致死量=1.5微克）注入小鼠脑内时均具有致死性，并会引起多动和震颤。本文及早期报告中描述的体外化学反应与帕金森病中神经黑素色素沉着的多巴胺能神经元中可能发生的反应的潜在相关性也进行了讨论。
