Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.
IUBMB Life. 2011 Dec;63(12):1087-93. doi: 10.1002/iub.538. Epub 2011 Nov 2.
The neurotransmitter dopamine is oxidized to its quinone (DA-Q), which at neutral pH undergoes intramolecular cyclization by 1,4-Michael addition, followed by oxidation to form leukochrome, then aminochrome, and finally neuromelanin. At lower pH, the amino group of DA is partially protonated, allowing the competitive intermolecular 1,4-Michael addition with nucleophiles in DNA to form the depurinating adducts, DA-6-N3Ade and DA-6-N7Gua. Catechol estrogen-3,4-quinones react by 1,4-Michael addition to form the depurinating 4-hydroxyestrone(estradiol)-1-N3Ade [4-OHE1(E2)-1-N3Ade] and 4-OHE1(E2)-1-N7Gua adducts, which are implicated in the initiation of breast and other human cancers. The effect of pH was studied by reacting tyrosinase-activated DA with DNA and measuring the formation of depurinating adducts. The most adducts were formed at pH 4, 5, and 6, and their level was nominal at pH 7 and 8. The N3Ade adduct depurinated instantaneously, but N7Gua had a half-life of 3 H. The slow loss of the N7Gua adduct is analogous to that observed in previous studies of natural and synthetic estrogens. The antioxidants N-acetylcysteine and resveratrol efficiently blocked formation of the DA-DNA adducts. Thus, slightly acidic conditions render competitive the reaction of DA-Q with DNA to form depurinating adducts. We hypothesize that formation of these adducts could lead to mutations that initiate Parkinson's disease. If so, use of N-acetylcysteine and resveratrol as dietary supplements may prevent initiation of this disease.
神经递质多巴胺被氧化为其醌（DA-Q），在中性 pH 下通过 1,4-迈克尔加成进行分子内环化，然后氧化形成白质，然后是氨基酚，最后是神经黑色素。在较低的 pH 下，DA 的氨基部分质子化，允许与 DNA 中的亲核试剂进行竞争的分子间 1,4-迈克尔加成，形成脱嘌呤加合物，DA-6-N3Ade 和 DA-6-N7Gua。儿茶酚雌激素-3,4-醌通过 1,4-迈克尔加成反应形成脱嘌呤 4-羟基雌酮（雌二醇）-1-N3Ade [4-OHE1(E2)-1-N3Ade] 和 4-OHE1(E2)-1-N7Gua 加合物，这些加合物与乳腺癌和其他人类癌症的起始有关。通过用酪氨酸酶激活的 DA 与 DNA 反应并测量脱嘌呤加合物的形成来研究 pH 的影响。在 pH 4、5 和 6 时形成了最多的加合物，在 pH 7 和 8 时其水平是名义上的。N3Ade 加合物立即脱嘌呤，但 N7Gua 的半衰期为 3 H。N7Gua 加合物的缓慢损失类似于先前对天然和合成雌激素的研究中观察到的情况。抗氧化剂 N-乙酰半胱氨酸和白藜芦醇有效地阻止了 DA-DNA 加合物的形成。因此，稍微酸性的条件使 DA-Q 与 DNA 反应形成脱嘌呤加合物具有竞争力。我们假设这些加合物的形成可能导致引发帕金森病的突变。如果是这样，使用 N-乙酰半胱氨酸和白藜芦醇作为膳食补充剂可能会阻止这种疾病的发生。
