Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells.
1. Zidovudine (3'-azido-2',3'-dideoxythymidine; AZT; ZDV) is a dideoxynucleoside analogue active against human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of ZDV to its putative active triphosphate form (ZDV triphosphate) in peripheral blood mononuclear cells and a lymphoblastoid cell line (h1A2v2). 2. Optimal conditions for intracellular phosphate formation in peripheral blood mononuclear cells occurred following a 72 h preincubation with the mitogen phytohaemagglutinin at a concentration of 10 micrograms ml-1. ZDV was metabolized predominantly to the monophosphate with smaller amounts of the di- and triphosphate anabolites. There was considerable inter- and intraindividual variability in phosphate formation in peripheral blood mononuclear cells. A similar pattern of phosphorylation was seen with the h1A2v2 lymphoblastoid cell line with ZDV monophosphate being the major metabolite. 3. With increasing interest in combination nucleoside analogue therapy in HIV-positive patients it is important to know if an interaction occurs at the level of phosphorylation. Neither dideoxyinosine (ddI) or dideoxycytidine (ddC) significantly reduced the intracellular phosphorylation of ZDV in either peripheral blood mononuclear cells or h1A2v2 cells. In contrast thymidine always gave marked inhibition (e.g. at 2.0 microM, 89% inhibition of total phosphate formation in peripheral blood mononuclear cells and 79% in h1A2v2 cells). It is, therefore, unlikely that in vivo either ddI or ddC will perturb ZDV phosphorylation.
Department of Pharmacology and Therapeutics, University of Liverpool.
G J
GJ
Veal
M J
MJ
Wild
M G
MG
Barry
D J
DJ
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D000704:Analysis of Variance; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D016049:Didanosine / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008213:Lymphocyte Activation; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D013936:Thymidine / Q000494:pharmacology; D016047:Zalcitabine / Q000494:pharmacology*; D015215:Zidovudine / Q000378:metabolism*
D010835:Phytohemagglutinins; D015215:Zidovudine; D016047:Zalcitabine; D016049:Didanosine; D013936:Thymidine