Prevention of neural tube defects by and toxicity of L-homocysteine in cultured postimplantation rat embryos.
Prevention of neural tube defects by and toxicity of L-homocysteine in cultured postimplantation rat embryos.
复制标题
DOI：
10.1002/tera.1420500506
复制
发表时间：
1994-11
期刊：
影响因子：
--
通讯作者：
L. A. Vanaerts;Henk J. Blom;Ronney A. Deabreu;Frans J. M. Trijbels;T. Eskes;Jenny H.J. Copius Peereboom-Stegeman;Jan Noordhoek
中科院分区：
文献类型：
--
作者：
L. A. Vanaerts;Henk J. Blom;Ronney A. Deabreu;Frans J. M. Trijbels;T. Eskes;Jenny H.J. Copius Peereboom-Stegeman;Jan Noordhoek
轻度高同型半胱氨酸血症是经常观察到的母亲谁生下的孩子与神经管缺陷（NTD）。在先前的研究中，我们发现l -同型半胱氨酸对培养的妊娠第10天（GD10）大鼠胚胎具有胚胎毒性，但未观察到ntd。因此，我们研究了l -同型半胱氨酸对神经板期（GD9.5）大鼠胚胎发育的影响。本研究的其他目的是研究l -同型半胱氨酸的胚胎毒性是否可以通过与其代谢相关的化合物来减弱，并阐明l -同型半胱氨酸胚胎毒性的机制。在GD9.5大鼠胚胎中，1和2 mm浓度的l -同型半胱氨酸没有毒性。相反，在这些浓度下，它促进了血清中大鼠胚胎的发育，而没有补充会导致胚胎中的NTDs。l -蛋氨酸在更低浓度下也有同样的预防作用，而亚叶酸（1 mM）对胚胎发育没有促进作用。n5 -甲基四氢叶酸（5-CH3-THF）（100微米）、l -丝氨酸（6毫米）和l -蛋氨酸（6毫米和12毫米）减弱了l -同型半胱氨酸（6毫米）对GD10大鼠胚胎的胚胎毒性。维生素B12（10微米）完全消除了l -同型半胱氨酸的胚胎毒性，这表明它是通过催化l -同型半胱氨酸自发氧化成毒性较小的l -同型半胱氨酸而介导的。在GD11大鼠胚胎中，L-和d -同型半胱氨酸在加入培养物（3 mM）时都很容易被吸收，胚胎s -腺苷型同型半胱氨酸（SAH）水平分别提高了14倍和3倍。这种差异被证明是由SAH水解酶的立体特异性偏好引起的。我们提出l -同型半胱氨酸胚胎毒性的基础是通过增加胚胎SAH水平抑制转甲基化反应。
Mild hyperhomocysteinemia is frequently observed in mothers who gave birth to a child with a neural tube defect (NTD). In a previous study we showed L-homocysteine was embryotoxic to gestational day 10 (GD10) rat embryos in culture, however, no NTDs were observed. We therefore investigated the effect of L-homocysteine on the development of neural plate stage (GD9.5) rat embryos. Other objectives of this study were investigation into whether the embryotoxicity of L-homocysteine could be attenuated by compounds related to its metabolism and clarification of the mechanism of L-homocysteine embryotoxicity. In GD9.5 rat embryos L-homocysteine was not toxic at 1- and 2-mM concentrations. Rather at these concentrations it promoted development of the rat embryos in serum that without supplementation caused NTDs in the embryos. L-Methionine had the same preventive effect at even lower concentrations, but folinic acid (1 mM) did not improve embryonic development. N5-Methyltetrahydrofolate (5-CH3-THF) (100 microM), L-serine (6 mM), and L-methionine (6 and 12 mM) attenuated the embryotoxicity of L-homocysteine (6 mM) in GD10 rat embryos. Vitamin B12 (10 microM) completely abolished the embryotoxicity of L-homocysteine, which was shown to be mediated by catalysis of the spontaneous oxidation of L-homocysteine to the less toxic L-homocystine. In GD11 rat embryos, both L- and D-homocysteine were readily taken up when added to the culture (3 mM) and increased embryonic S-adenosylhomocysteine (SAH) levels 14- and 3-fold, respectively. This difference was shown to be caused by the stereospecific preference of SAH hydrolase. We propose the basis for L-homocysteine embryotoxicity is an inhibition of transmethylation reactions by increased embryonic SAH levels.