Department of Internal Medicine, Genome and Biomedical Sciences Facility, University of California, Davis, CA 95616, USA.
Mol Nutr Food Res. 2010 May;54(5):693-709. doi: 10.1002/mnfr.200900575.
Rodents fed alpha-tocopherol (alphaT)-depleted diets develop neuromuscular deficits. Unequivocal role of alphaT in the prevention of these deficits is confounded by possible neurotoxic oxidant products generated, ex vivo in alphaT-depleted diets. The discovery that large doses of alphaT could ameliorate neuromuscular deficits, attributed to very low serum alphaT caused by mutations in either the microsomal triglyceride transfer protein or the alphaT-transfer protein (alphaTTP), underscores the necessity of alphaT for neuromuscular health in humans. The discovery of human alphaTTP provided physiological relevance to biochemical data from rodents documenting alphaT-binding transfer protein, expressed exclusively in liver. The cloning of alphaTTP gene and the creation of alphaTTP-knockout mice allowed to achieve severe systemic alphaT deficiency in brain and muscles, possibly at birth, eliminating the possible confounding effects of ex vivo-generated oxidant products in vitamin E-stripped diets. alphaTTP-knockout mice have proven useful models to discover alphaT-regulated phenotypes and molecular actions of alphaT in vivo. The results suggest that antioxidant and non-antioxidant actions of alphaT in vivo may not be mutually exclusive. These studies also suggest that low levels of dietary alphaT can achieve in excess of nanomolar alphaT levels in tissues and maintain normal neuromuscular functions. This is consistent with biochemical and crystallographic data of alpha-TTP and of other alphaT-binding proteins that have dissociation constants in nanomolar range. Molecular mechanisms that cause a long delay for the development of deficiency symptoms remain enigmatic. It is likely that alphaT is metabolically stable in post-mitotic neurons and myocytes and, if it undergoes redox-cycling in vivo, a large repertoire of alphaT-regenerating systems maintains its biological activity before it is totally depleted.
以α-生育酚（αT）耗尽饮食喂养的啮齿动物会出现神经肌肉缺陷。αT 预防这些缺陷的明确作用因体外生成的可能神经毒性氧化剂产物而变得复杂，这些产物是在αT 耗尽饮食中产生的。发现大剂量的αT 可以改善神经肌肉缺陷，这归因于微粒体甘油三酯转移蛋白或αT 转移蛋白（αTTP）突变导致的血清αT 极低，这突出表明αT 对人类神经肌肉健康的必要性。人类αTTP 的发现为来自啮齿动物的生化数据提供了生理相关性，这些数据记录了仅在肝脏中表达的αT 结合转移蛋白。αTTP 基因的克隆和αTTP 敲除小鼠的创建使得在大脑和肌肉中实现了严重的系统性αT 缺乏，可能在出生时就发生了，消除了维生素 E 剥夺饮食中外生氧化剂产物的可能混杂影响。αTTP 敲除小鼠已被证明是有用的模型，可以在体内发现αT 调节的表型和αT 的分子作用。结果表明，αT 在体内的抗氧化和非抗氧化作用可能并不相互排斥。这些研究还表明，低水平的饮食αT 可以在组织中达到超过纳米摩尔水平的αT 水平，并维持正常的神经肌肉功能。这与α-TTP 和其他αT 结合蛋白的生化和晶体学数据一致，这些数据的解离常数在纳米摩尔范围内。导致缺乏症状发展出现长时间延迟的分子机制仍然是个谜。αT 在有丝分裂后神经元和肌细胞中可能具有代谢稳定性，如果它在体内经历氧化还原循环，那么大量的αT 再生系统可以在其完全耗尽之前维持其生物活性。
