Maeda N, Hagihara H, Nakata Y, Hiller S, Wilder J, Reddick R
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):841-6. doi: 10.1073/pnas.97.2.841.
By inactivating the gene for L-gulono-gamma-lactone oxidase, a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C. Regular chow, containing about 110 mg/kg of vitamin C, is unable to support the growth of the mutant mice, which require L-ascorbic acid supplemented in their drinking water (330 mg/liter). Upon withdrawal of supplementation, plasma and tissue ascorbic acid levels decreased to 10-15% of normal within 2 weeks, and after 5 weeks the mutants became anemic, began to lose weight, and die. Plasma total antioxidative capacities were approximately 37% normal in homozygotes after feeding the unsupplemented diet for 3-5 weeks. As plasma ascorbic acid decreased, small, but significant, increases in total cholesterol and decreases in high density lipoprotein cholesterol were observed. The most striking effects of the marginal dietary vitamin C were alterations in the wall of aorta, evidenced by the disruption of elastic laminae, smooth muscle cell proliferation, and focal endothelial desquamation of the luminal surface. Thus, marginal vitamin C deficiency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on the pathogenesis of vascular diseases. Breeding the vitamin C-dependent mice with mice carrying defined genetic mutations will provide numerous opportunities for systematic studies of the role of antioxidants in health and disease.
通过使抗坏血酸合成中的关键酶L-古洛糖酸-γ-内酯氧化酶的基因失活，我们培育出了像人类一样依赖膳食维生素C的小鼠。含有约110毫克/千克维生素C的常规饲料无法支持突变小鼠的生长，这些小鼠需要在饮用水中补充L-抗坏血酸（330毫克/升）。停止补充后，血浆和组织中的抗坏血酸水平在2周内降至正常水平的10 - 15%，5周后突变小鼠出现贫血、体重开始减轻并死亡。在喂食无补充饲料3 - 5周后，纯合子小鼠的血浆总抗氧化能力约为正常水平的37%。随着血浆抗坏血酸水平降低，观察到总胆固醇有小幅但显著的升高，高密度脂蛋白胆固醇降低。膳食中维生素C边缘性缺乏最显著的影响是主动脉壁的改变，表现为弹性膜破裂、平滑肌细胞增殖以及管腔表面局灶性内皮脱落。因此，边缘性维生素C缺乏会影响无法合成抗坏血酸的小鼠的血管完整性，对血管疾病的发病机制可能产生深远影响。将依赖维生素C的小鼠与携带特定基因突变的小鼠进行杂交，将为系统研究抗氧化剂在健康和疾病中的作用提供众多机会。
