Turriziani O, Simeoni E, Dianzani F, Antonelli G
Institute of Virology, University La Sapienza, Rome, Italy.
Antivir Ther. 1998;3(3):191-4.
Stavudine (d4T) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. It is known that stavudine is metabolized in cells to the mono-, di- and triphosphate nucleotides but the enzymes responsible for its phosphorylation are as yet unidentified. In particular, there are conflicting results concerning the role of thymidine kinase 1 (TK1) in stavudine metabolism. To gain new insights into this phenomenon we analysed the antiviral activity of stavudine in a TK1-deficient, resistant cell line. The results indicate that TK1 is responsible for the phosphorylation of stavudine but it is not the only enzyme involved in its activation. The other enzyme(s) that might be involved in the metabolism of stavudine, however, are not able to phosphorylate stavudine with the same efficiency as TK1. Since it has been shown that prolonged treatment with zidovudine may induce an in vivo defect in TK1 activity, it is tempting to speculate that patients treated for a long time with zidovudine could be resistant to further treatment with stavudine.
司他夫定（d4T）是人类免疫缺陷病毒1型（HIV-1）逆转录酶的强效抑制剂。已知司他夫定在细胞内代谢为单磷酸、二磷酸和三磷酸核苷酸，但负责其磷酸化的酶尚未确定。特别是，关于胸苷激酶1（TK1）在司他夫定代谢中的作用存在相互矛盾的结果。为了深入了解这一现象，我们分析了司他夫定在TK1缺陷的耐药细胞系中的抗病毒活性。结果表明，TK1负责司他夫定的磷酸化，但它不是参与其激活的唯一酶。然而，可能参与司他夫定代谢的其他酶不能像TK1那样高效地将司他夫定磷酸化。由于已表明长期使用齐多夫定治疗可能会导致体内TK1活性缺陷，因此很容易推测长期接受齐多夫定治疗的患者可能对司他夫定的进一步治疗产生耐药性。
