Long-term AZT Exposure Alters the Metabolic Capacity of Cultured Human Lymphoblastoid Cells

• DOI: 10.1093/toxsci/kfq023
• Publication Date: 2010-01-28T02:10:02Z
• Authors: Ofelia A. Olivero; Irma L. Vazquez; Catherine C. Cooch; Jessica Ming; Emily Keller; Mia Yu; Jennifer P. Boroj...; Hannan M. Braun; Edward McKee; Miriam C. Poirier
• Keywords: Lymphoblast; Thymidine; Thymidine kinase

The antiretroviral efficacy of 3′-azido-3′-deoxythymidine (AZT) is dependent upon intracellular mono-, di-, and triphosphorylation incorporation into DNA in place thymidine. Thymidine kinase 1 (TK-1) catalyzes the first step this pathway. MOLT-3, human lymphoblastoid cells, were exposed to AZT continuously for 14 passages (P1–P14) cultured an additional (P15–P28) without AZT. Progressive irreversible depletion enzymatically active form TK-1 24-kDa monomer with loss protein was demonstrated during P1–P5 exposure. From P15 P28, both 24- 48-kDa forms undetectable a tetrameric 96-kDa present. AZT-DNA observed values 150, 133, 108 molecules AZT/106 nucleotides at 10μM plasma-equivalent dose P1, P5, P14, respectively. An exposure-related increase frequency micronuclei (MN) cells either 10 or 800μM P1–P14. Analysis cell cycle profile revealed accumulation S-phase decrease G1-phase exposure passages. When MOLT-3 grown AZT-free media (P15–P29), there reduction MN formation; however, persistence delay unchanged. These data suggest that addition known mutagenic mechanisms, may become resistant partially through inactivation modulation components.