Thijssen H H, Drittij-Reijnders M J
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Br J Haematol. 1993 Aug;84(4):681-5. doi: 10.1111/j.1365-2141.1993.tb03146.x.
Vitamin K-dependent parameters in human liver samples were investigated to find a clue to the inter-individual differences in sensitivity for oral anticoagulants. Vitamin K epoxide reductase and vitamin K-dependent carboxylase activity differed 2-3-fold between the samples. Microsomal warfarin binding correlated significantly with the reductase activity. Microsomal vitamin K epoxide reductase of the different samples showed equal sensitivity for warfarin inhibition, I50 about 0.1 microM. Vitamin K epoxide reductase activity stimulated by NADH/lipoamide and microsomal lipoamide dehydrogenase activity showed higher inter-subject variability than the reductase activity by itself. Liver vitamin K1 levels varied 4-5-fold. Total and liver microsomal vitamin K1 levels were correlated. One of the liver samples was obtained from a donor anticoagulated with phenprocoumon and additionally treated with vitamin K1. High levels of the vitamin and its epoxide were present. Phenprocoumon was essentially irreversibly bound to the microsomes. In general the results confirm inter-individual differences in the hepatic vitamin K-dependent systems; the differences as such were found to be small. However, as the various parameters can work synergistically in the same direction, they may well account for the wide dose range observed in oral anticoagulant therapy.
研究了人肝脏样本中维生素K依赖参数，以寻找口服抗凝剂个体敏感性差异的线索。样本间维生素K环氧化物还原酶和维生素K依赖羧化酶活性相差2至3倍。微粒体华法林结合与还原酶活性显著相关。不同样本的微粒体维生素K环氧化物还原酶对华法林抑制表现出相同的敏感性，半数抑制浓度（I50）约为0.1微摩尔。由烟酰胺腺嘌呤二核苷酸（NADH）/硫辛酰胺刺激的维生素K环氧化物还原酶活性和微粒体硫辛酰胺脱氢酶活性比还原酶活性本身表现出更高的个体间变异性。肝脏维生素K1水平相差4至5倍。总维生素K1水平与肝脏微粒体维生素K1水平相关。其中一个肝脏样本取自用苯丙香豆素抗凝并额外用维生素K1治疗的供体。样本中存在高水平的维生素及其环氧化物。苯丙香豆素基本上不可逆地与微粒体结合。总体而言，结果证实了肝脏维生素K依赖系统存在个体间差异；发现这种差异很小。然而，由于各种参数可在同一方向协同作用，它们很可能解释了口服抗凝治疗中观察到的广泛剂量范围。
