Michalak A, Qureshi I A
Service de Génétique Médicale, Hôpital Ste-Justine, Montréal, Québec, Canada.
Biomed Pharmacother. 1995;49(7-8):350-7. doi: 10.1016/0753-3322(96)82664-3.
The aim of the present study, was to establish the hepatic profile of acyl-coenzyme A (acyl-CoA) in relation to the hepatic profile of acylcarnitines in chronically hyperammonemic spf mice (hereditary deficiency in ornithine transcarbamylase) treated with sodium benzoate alone or in combination with L-carnitine. The muscular profile of the acylcarnitines and the stability of sarcolemma were also assessed in the same mice. Following administration of sodium benzoate, we observed decreases in hepatic total and free coenzyme A and in acetyl-CoA, which was accompanied by an increase in hepatic acyl-CoA. This treatment also resulted in increased free carnitine, decreased total carnitine, and decreased short and medium chain acylcarnitines in the liver. Increases in plasma creatine kinase levels, muscular free, total, and in short and medium chain acylcarnitines were also observed in this treatment group. In mice receiving a combination of sodium benzoate and L-carnitine, increases in free and total coenzyme A, acetyl-CoA and in free, total and esterified hepatic carnitines were observed. In this treatment group, the plasma level of creatine kinase was found to be reduced, while the free muscular carnitine was increased. Our results indicate that sodium benzoate is implicated in the decrease of total hepatic coenzyme A, through either an inhibition of CoA synthesis or activation of its degradation. The distribution of hepatic coenzyme-A and of hepatic and muscular carnitine (free or esterified) is altered following administration of sodium benzoate which results in a further destabilization of the sarcolemma induced by hyperammonemia. Supplemental treatment with L-carnitine was shown to have a positive effect by increasing hepatic coenzyme A and carnitine levels and restoring the stability of the sarcolemma caused by the treatment of sodium benzoate alone.
本研究的目的是确定在单独使用苯甲酸钠或与左旋肉碱联合使用治疗的慢性高氨血症spf小鼠（鸟氨酸转氨甲酰酶遗传性缺陷）中，酰基辅酶A（acyl-CoA）的肝脏概况与酰基肉碱的肝脏概况之间的关系。还评估了相同小鼠中酰基肉碱的肌肉概况和肌膜的稳定性。给予苯甲酸钠后，我们观察到肝脏中总辅酶A和游离辅酶A以及乙酰辅酶A减少，同时肝脏中酰基辅酶A增加。这种治疗还导致肝脏中游离肉碱增加、总肉碱减少以及短链和中链酰基肉碱减少。在该治疗组中还观察到血浆肌酸激酶水平升高以及肌肉中游离、总以及短链和中链酰基肉碱增加。在接受苯甲酸钠和左旋肉碱联合治疗的小鼠中，观察到游离和总辅酶A、乙酰辅酶A以及游离、总以及酯化肝脏肉碱增加。在该治疗组中，发现血浆肌酸激酶水平降低，而肌肉中游离肉碱增加。我们的结果表明，苯甲酸钠通过抑制辅酶A合成或激活其降解参与了肝脏总辅酶A的减少。给予苯甲酸钠后，肝脏辅酶A以及肝脏和肌肉中肉碱（游离或酯化）的分布发生改变，这导致高氨血症诱导的肌膜进一步不稳定。结果表明，补充左旋肉碱具有积极作用，可增加肝脏辅酶A和肉碱水平，并恢复仅用苯甲酸钠治疗引起的肌膜稳定性。
