Jacobsson B, Britton S, Törnevik Y, Eriksson S
Department of Infectious Diseases, Huddinge Hospital, Sweden.
Biochem Pharmacol. 1998 Aug 1;56(3):389-95. doi: 10.1016/s0006-2952(98)00032-x.
Nucleosides and nucleoside analogs are anabolised to their triphosphates by intracellular kinases. The anti-HIV analogue zidovudine (AZT) is phosphorylated by cytosolic thymidine kinase 1 (TK1), thymidylate kinase (dTMPK), and nucleoside diphosphate kinase. It is known that dTMPK is one of the rate-limiting steps in the activation of zidovudine. The activities of TK1, dTMPK, and deoxycytidine kinase (dCK) were determined in extracts of in vitro activated peripheral blood mononuclear cells from HIV-infected patients and healthy noninfected individuals. dTMPK activity was 10-fold lower and TK1 activity was five-fold lower in extracts from infected as compared to uninfected persons. Deoxycytidine kinase activities in the extracts from both groups were very similar. Differences in in vitro activation, as determined by flow cytometry, of the peripheral lymphocytes were not responsible for the decreased TK1 and dTMPK activities. A reduced level of intracellular azido-dideoxythymidinetriphosphate in activated mononuclear cells from HIV-infected patients was also observed. The low levels of TK1 and dTMPK in lymphocytes from HIV-infected patients may be related to the anergy phenomenon observed as a result of HIV infection. This effect should also be considered in the development of new anti-HIV drugs.
核苷和核苷类似物通过细胞内激酶被代谢为其三磷酸形式。抗HIV类似物齐多夫定（AZT）由胞质胸苷激酶1（TK1）、胸苷酸激酶（dTMPK）和核苷二磷酸激酶磷酸化。已知dTMPK是齐多夫定激活过程中的限速步骤之一。在来自HIV感染患者和健康未感染个体的体外激活外周血单核细胞提取物中测定了TK1、dTMPK和脱氧胞苷激酶（dCK）的活性。与未感染个体相比，感染个体提取物中的dTMPK活性低10倍，TK1活性低5倍。两组提取物中的脱氧胞苷激酶活性非常相似。通过流式细胞术测定的外周淋巴细胞体外激活差异与TK1和dTMPK活性降低无关。在来自HIV感染患者的激活单核细胞中也观察到细胞内叠氮脱氧胸苷三磷酸水平降低。HIV感染患者淋巴细胞中TK1和dTMPK水平较低可能与HIV感染导致的无反应现象有关。在开发新的抗HIV药物时也应考虑这种效应。
