Effect of nucleoside and nucleotide reverse transcriptase inhibitors of HIV on endogenous nucleotide pools.
作者： Jennifer E Vela , Michael D Miller , Gerald R Rhodes , Adrian S Ray , None
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摘要: BACKGROUND Alterations in endogenous nucleotide pools as a result of HIV therapy with nucleoside and reverse transcriptase inhibitors (N[t]RTIs) is proposed mechanism for therapy-related adverse events drug interactions resulting treatment failure. In vitro studies were performed order to understand the effect N(t)RTIs on pools. METHODS The T-cell line CEM-CCRF was treated control antimetabolites or abacavir, didanosine, lamivudine, tenofovir (TFV) zidovudine (AZT), either alone combination. levels natural 2'-deoxynucleoside triphosphates (dNTP) ribonucleoside triphophosphates determined by liquid chromatography coupled triple quadrupole mass spectrometry. RESULTS Antimetabolites altered manner consistent their known mechanisms action. AZT only N(t)RTI that significantly dNTP incubation 10 microM AZT, combination other N(t)RTIs, increased 2'-deoxyadenosine triphosphate, 2'-deoxyguanosine triphosphate thymidine up 1.44-fold concentrations observed untreated cells. At higher than pharmacological evidence inhibition 2'-deoxycytidylate deaminase enzymes involved salvage also observed. Phosphorylated metabolites TFV are inhibit purine phosphorylase (PNP). However, contrast potent PNP inhibitor, unable alter intracellular upon addition exogenous 2'-deoxyguanosine. CONCLUSIONS have potential pools; however, at pharmacologically relevant concentrations, tested combinations did not an notable exception AZT.
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