Mawal Y R, Rama Rao K V, Qureshi I A
Division of Medical Genetics, Sainte-Justine Hospital and University of Montréal, Québec, Canada.
Biochem Pharmacol. 1998 Jun 1;55(11):1853-60. doi: 10.1016/s0006-2952(98)00051-3.
The sparse fur (spf) mutant mouse, with an X-linked ornithine transcarbamylase deficiency, is a model of congenital hyperammonemia in children. Our earlier studies indicated a deficiency of hepatic carnitine, CoA-SH, acetyl CoA, and ATP in spf mice. We have now studied the effects of a 7-day treatment with acetyl-L-carnitine (ALCAR) in the spf/Y mice on the activity and expression of the respiratory chain enzyme cytochrome c oxidase (COX; EC 1.9.3.1). We found decreased hepatic activity and expression of COX in the untreated hyperammonemic spf/Y mice, which was restored upon ALCAR treatment. Because COX is a mitochondrial membrane protein, we also carried out studies to explain the mechanism of ALCAR through its effect on membrane stability. Our results indicate a decrease of the mitochondrial membrane cholesterol/phospholipid molar ratio (CHOL/PL ratio) with the activity and expression of COX in untreated spf/Y mice. While ALCAR treatment normalized the ratios, it also restored the hepatic ATP production to normal. To study further if there was any effect of ALCAR on the mitochondrial matrix urea cycle enzymes, we measured the activity and expression of mutant ornithine transcarbamylase (OTC; EC 2.1.3.3) and normal carbamyl phosphate synthase-I (CPS-I; EC 6.3.4.16) in spf/Y mice. There was no general effect on the specific activities of the matrix enzymes upon ALCAR treatment, although their mRNA levels were enhanced. Our studies point towards the feasibility of an ALCAR treatment in conjunction with other treatment modalities, e.g. sodium benzoate and/or arginine, to improve the availability of cellular ATP and to counteract the effects of hereditary hyperammonemic syndromes in children.
稀疏毛（spf）突变小鼠存在X连锁鸟氨酸转氨甲酰酶缺乏，是儿童先天性高氨血症的模型。我们早期的研究表明，spf小鼠肝脏中肉碱、辅酶A（CoA-SH）、乙酰辅酶A和三磷酸腺苷（ATP）缺乏。我们现在研究了在spf/Y小鼠中用乙酰-L-肉碱（ALCAR）进行7天治疗对呼吸链酶细胞色素c氧化酶（COX；EC 1.9.3.1）活性和表达的影响。我们发现，未经治疗的高氨血症spf/Y小鼠肝脏中COX活性和表达降低，而ALCAR治疗后恢复。由于COX是一种线粒体膜蛋白，我们还进行了研究以解释ALCAR通过其对膜稳定性的影响发挥作用的机制。我们的结果表明，未经治疗的spf/Y小鼠中线粒体膜胆固醇/磷脂摩尔比（CHOL/PL比）降低，同时COX活性和表达也降低。虽然ALCAR治疗使该比例恢复正常，但它也使肝脏ATP生成恢复到正常水平。为了进一步研究ALCAR对线粒体基质尿素循环酶是否有任何影响，我们测量了spf/Y小鼠中突变型鸟氨酸转氨甲酰酶（OTC；EC 2.1.3.3）和正常氨甲酰磷酸合成酶-I（CPS-I；EC 6.3.4.16）的活性和表达。ALCAR治疗后，对基质酶的比活性没有普遍影响，尽管它们的mRNA水平有所提高。我们的研究表明，ALCAR与其他治疗方式（如苯甲酸钠和/或精氨酸）联合治疗，对于提高细胞ATP的可用性以及对抗儿童遗传性高氨血症综合征的影响具有可行性。
