Ning C, Reynolds R, Chen J, Yager C, Berry G T, Leslie N, Segal S
Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4318, USA.
Mol Genet Metab. 2001 Apr;72(4):306-15. doi: 10.1006/mgme.2001.3152.
Mice deficient in galactose-1-phosphate uridyltransferase (GALT) demonstrate abnormal galactose metabolism but no obvious clinical phenotype. To further dissect the pathways of galactose metabolism in these animals, galactose oxidation and metabolite levels were studied in 16-day-old sucklings and the effect of a 4 week prior exposure to a 40% glucose or 40% galactose diet was determined in 7-week-old mice. Suckling GALT-deficient (G/G) mice slowly oxidized [1-14C]galactose to 14CO2, 4.0% of the dose when fed and 7.9% when fasted compared to normal animals 38.3 and 36.4% in 4 h, respectively. Plasma of G/G sucklings contained 11.1 mM galactose and erythrocyte galactose 1-phosphate levels were 28.2 and 31.9 mg/dl packed cells. Galactose, galactitol, galactonate, and galactose 1-phosphate were found in G/G suckling mouse tissues. The tissue galactose concentrations were 10% or less of that in plasma, suggesting that there was limited cellular entry of galactose. In 7-week-old fasted mice with 4 weeks prior exposure to glucose or galactose-containing diet, 4-h oxidation was 12.9 and 15.0% of the administered radiolabeled galactose, respectively. Normal animals oxidized 33.9 and 37.9% of the dose when fed the same diets, respectively. The ability of G/G mice to oxidize galactose in the absence of GALT activity suggests the presence of alternate metabolic pathways for galactose disposition. G/G mice fed the galactose-free 40% glucose diet had erythrocyte galactose 1-phosphate levels ranging from 6.4 to 17.7 mg/dl packed cells and detectable galactose and galactose metabolites in tissues, suggesting that these animals endogenously produced galactose. The plasma of 40% galactose-fed G/G mice contained 9.1 mM galactose with red blood cell galactose 1-phosphate averaging 43.6 mg/dl. Tissues of these animals also contained high levels of galactose and galactose 1-phosphate. Liver contained over 4 micromol/g galactonate but little galactitol. Despite the elevated galactose and galactose 1-phosphate, the animals tolerated the high-galactose diet and were indistinguishable from normal animals, exhibiting no manifestations of galactose toxicity seen in human GALT-deficient galactosemia. The data suggest that high galactose 1-phosphate levels do not cause galactose toxicity and that high galactitol in combination with galactose 1-phosphate may be a prerequisite. Absence of GALT appears necessary but insufficient to produce human galactosemic phenotype.
缺乏1-磷酸半乳糖尿苷转移酶（GALT）的小鼠表现出异常的半乳糖代谢，但无明显临床表型。为了进一步剖析这些动物体内半乳糖代谢途径，研究了16日龄乳鼠的半乳糖氧化和代谢物水平，并测定了7周龄小鼠在4周前暴露于40%葡萄糖或40%半乳糖饮食后的影响。与正常动物相比，乳鼠GALT缺陷（G/G）小鼠将[1-14C]半乳糖缓慢氧化为14CO2，喂食时为剂量的4.0%，禁食时为7.9%，而正常动物在4小时内分别为38.3%和36.4%。G/G乳鼠血浆中半乳糖含量为11.1 mM，红细胞1-磷酸半乳糖水平为每毫升压积细胞28.2和31.9毫克。在G/G乳鼠组织中发现了半乳糖、半乳糖醇、半乳糖酸和1-磷酸半乳糖。组织中的半乳糖浓度为血浆中的10%或更低，表明半乳糖进入细胞的量有限。在7周龄禁食小鼠中，4周前暴露于含葡萄糖或半乳糖饮食，4小时氧化分别为给予的放射性标记半乳糖的12.9%和15.0%。正常动物在喂食相同饮食时分别氧化剂量的33.9%和37.9%。G/G小鼠在缺乏GALT活性的情况下氧化半乳糖的能力表明存在半乳糖处置的替代代谢途径。喂食不含半乳糖的40%葡萄糖饮食后，G/G小鼠红细胞1-磷酸半乳糖水平为每毫升压积细胞6.4至17.7毫克，组织中可检测到半乳糖和半乳糖代谢物，表明这些动物内源性产生半乳糖。喂食40%半乳糖的G/G小鼠血浆中半乳糖含量为9.1 mM，红细胞1-磷酸半乳糖平均为43.6毫克/毫升。这些动物的组织中也含有高水平的半乳糖和1-磷酸半乳糖。肝脏中半乳糖酸含量超过4微摩尔/克，但半乳糖醇含量很少。尽管半乳糖和1-磷酸半乳糖水平升高，但这些动物耐受高半乳糖饮食，与正常动物无差异，未表现出人类GALT缺陷型半乳糖血症中所见的半乳糖毒性表现。数据表明，高1-磷酸半乳糖水平不会导致半乳糖毒性，高半乳糖醇与1-磷酸半乳糖结合可能是一个先决条件。GALT的缺失似乎是产生人类半乳糖血症表型的必要但不充分条件。
