Thijssen Henk H, Soute Berry A, Vervoort Lily M, Claessens Jolanda G
Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, P.O Box 616, 6200 MD Maastricht, The Netherlands.
Thromb Haemost. 2004 Oct;92(4):797-802. doi: 10.1160/TH04-02-0109.
Paracetamol (acetaminophen) is generally considered to be the analgesic of choice for patients undergoing oral anticoagulant therapy. Occasionally, however, interactions have been reported with therapeutic doses of the analgesic, e.g. if the drug is taken for a longer period of time. The mechanism of this interaction is not clearly understood. We investigated the effects of paracetamol and its toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) on in vitro vitamin K-dependent gamma-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activities. Paracetamol had no effect in either enzymatic reactions. NAPQI, on the other hand, appeared to interfere with VKD carb activity via two mechanisms; 1) oxidation of the cofactor vitamin K-hydroquinone, 2) inactivation of the enzyme. The inactivation, in micromolar ranges, is not reversible and may be the result of covalent binding of NAPQI with functional amino acids. NAPQI also inhibited VKOR, but at higher concentrations. Unexpectedly, N-acetylcysteine was found to inhibit VKOR activity at concentrations that are obtained during rescue therapy of paracetamol intoxication. We conclude that, the potentiation of the oral anticoagulant effect by paracetamol is likely to result from NAPQI-induced inhibition of enzymes of the vitamin K cycle, particularly VKD-carb.
对乙酰氨基酚通常被认为是接受口服抗凝治疗患者的首选镇痛药。然而，偶尔也有报道称该镇痛药的治疗剂量会产生相互作用，例如药物服用时间较长时。这种相互作用的机制尚不清楚。我们研究了对乙酰氨基酚及其有毒代谢物N - 乙酰 - 对苯醌亚胺（NAPQI）对体外维生素K依赖性γ - 羧化酶（VKD - carb）和维生素K环氧化物还原酶（VKOR）活性的影响。对乙酰氨基酚在两种酶促反应中均无作用。另一方面，NAPQI似乎通过两种机制干扰VKD - carb活性：1）辅因子维生素K - 氢醌的氧化，2）酶的失活。在微摩尔范围内的失活是不可逆的，可能是NAPQI与功能性氨基酸共价结合的结果。NAPQI也抑制VKOR，但浓度较高。出乎意料的是，发现N - 乙酰半胱氨酸在对乙酰氨基酚中毒抢救治疗期间达到的浓度下会抑制VKOR活性。我们得出结论，对乙酰氨基酚增强口服抗凝作用可能是由于NAPQI诱导的维生素K循环酶，特别是VKD - carb的抑制。
