Brass E P, Fennessey P V, Miller L V
Biochem J. 1986 May 15;236(1):131-6. doi: 10.1042/bj2360131.
The present study was designed to study the interaction of propionic acid and carnitine on oxidative metabolism by isolated rat hepatocytes. Propionic acid (10 mM) inhibited hepatocyte oxidation of [1-14C]-pyruvate (10 mM) by 60%. This inhibition was not the result of substrate competition, as butyric acid had minimal effects on pyruvate oxidation. Carnitine had a small inhibitory effect on pyruvate oxidation in the hepatocyte system (210 +/- 19 and 184 +/- 18 nmol of pyruvate/60 min per mg of protein in the absence and presence of 10 mM-carnitine respectively; means +/- S.E.M., n = 10). However, in the presence of propionic acid (10 mM), carnitine (10 mM) increased the rate of pyruvate oxidation by 19%. Under conditions where carnitine partially reversed the inhibitory effect of propionic acid on pyruvate oxidation, formation of propionylcarnitine was documented by using fast-atom-bombardment mass spectroscopy. Propionic acid also inhibited oxidation of [1-14C]palmitic acid (0.8 mM) by hepatocytes isolated from fed rats. The degree of inhibition caused by propionic acid was decreased in the presence of 10 mM-carnitine (41% inhibition in the absence of carnitine, 22% inhibition in the presence of carnitine). Propionic acid did not inhibit [1-14C]palmitic acid oxidation by hepatocytes isolated from 48 h-starved rats. These results demonstrate that propionic acid interferes with oxidative metabolism in intact hepatocytes. Carnitine partially reverses the inhibition of pyruvate and palmitic acid oxidation by propionic acid, and this reversal is associated with increased propionylcarnitine formation. The present study provides a metabolic basis for the efficacy of carnitine in patients with abnormal organic acid accumulation, and the observation that such patients appear to have increased carnitine requirements ('carnitine insufficiency').
本研究旨在探讨丙酸与肉碱对分离的大鼠肝细胞氧化代谢的相互作用。丙酸（10 mM）可抑制肝细胞对[1-14C] - 丙酮酸（10 mM）的氧化达60%。这种抑制并非底物竞争的结果，因为丁酸对丙酮酸氧化的影响极小。肉碱对肝细胞系统中丙酮酸的氧化有轻微抑制作用（在不存在和存在10 mM肉碱的情况下，每毫克蛋白质每60分钟丙酮酸氧化量分别为210±19和184±18 nmol；均值±标准误，n = 10）。然而，在存在丙酸（10 mM）的情况下，肉碱（10 mM）可使丙酮酸氧化速率提高19%。在肉碱部分逆转丙酸对丙酮酸氧化抑制作用的条件下，通过快速原子轰击质谱法证实了丙酰肉碱的形成。丙酸还抑制了从喂食大鼠分离的肝细胞对[1-14C] - 棕榈酸（0.8 mM）的氧化。在存在10 mM肉碱的情况下，丙酸引起的抑制程度降低（不存在肉碱时抑制率为41%，存在肉碱时为22%）。丙酸不抑制从饥饿48小时的大鼠分离的肝细胞对[1-14C] - 棕榈酸的氧化。这些结果表明，丙酸会干扰完整肝细胞中的氧化代谢。肉碱可部分逆转丙酸对丙酮酸和棕榈酸氧化的抑制作用，且这种逆转与丙酰肉碱形成增加有关。本研究为肉碱对有机酸蓄积异常患者的疗效提供了代谢基础，以及此类患者似乎肉碱需求增加（“肉碱不足”）这一观察结果的依据。
