右旋甲状腺素对Ⅱ相代谢酶UGT2B17抑制的研究

The Inhibition of PhaseⅡDrug-metabolizing Enzymes UDP-glucuronosyltransferases UGT2B17 by D-thyroxine

尿苷二磷酸葡萄糖醛酸转移酶(UGTs)主要参与体内多种物质代谢,是人体内最重要的Ⅱ相代谢酶.UGT2B17是UGTs的一种亚型,当UGT2B17的活性被抑制,其代谢的多种内源性和外源性物质在体内蓄积,产生相应的毒副作用.本实验建立经典的体外孵育体系,采用4-甲基伞形酮(4-MU)作为反应底物,测得右旋甲状腺素存在的情况下,UGT2B17对4-MU代谢的残余活性小于20%,后续实验测得抑制动力学参数Ki值为0.064μmol/L.所以右旋甲状腺素对UGT2B17的活性有强烈的抑制作用.因此在临床中应用含右旋甲状腺素的药物时应注意其剂量,避免引起其对UGT2B17活性的抑制,导致毒副作用.

UDP-glucuronosyltransferases(UGTs) are mainly involved in the metabolism of a variety of substances in the body. UGTs are importantⅡphase metabolic enzyme in ours body. UGT2 B17 is one of the most important UGTs. When the activity of UGT2 B17 is inhibited its metabolism of a variety of endogenous and exogenous substances accumulate in the body, resulting in corresponding toxic side effects. In the present study, a classical in vitro incubation system was established and 4-methylumbelliferone(4-MU)was used as the reaction substrate. The residual activity of UGT2 B17 to 4-MU metabolism was less than20% under the condition of the existence of D-thyroxine, and the Ki of inhibition kinetic parameters was0.064 μmol/L in the experiments. D-thyroxine has a strong inhibitory effect on the activity of UGT2 B17.Therefore, application of drugs containing D-thyroxine in clinical should pay attention to its dosage, to avoid causing its inhibition of UGT2 B17 activity and toxic side effects.