Long-term AZT exposure alters the metabolic capacity of cultured human lymphoblastoid cells.

Toxicological Sciences : an Official Journal of the Society of Toxicology
O A OliveroM C Poirier

Abstract

The antiretroviral efficacy of 3'-azido-3'-deoxythymidine (AZT) is dependent upon intracellular mono-, di-, and triphosphorylation and incorporation into DNA in place of thymidine. Thymidine kinase 1 (TK-1) catalyzes the first step of this pathway. MOLT-3, human lymphoblastoid cells, were exposed to AZT continuously for 14 passages (P(1)-P(14)) and cultured for an additional 14 passages (P(15)-P(28)) without AZT. Progressive and irreversible depletion of the enzymatically active form of the TK-1 24-kDa monomer with loss of active protein was demonstrated during P(1)-P(5) of AZT exposure. From P(15) to P(28), both the 24- and the 48-kDa forms of TK-1 were undetectable and a tetrameric 96-kDa form was present. AZT-DNA incorporation was observed with values of 150, 133, and 108 molecules of AZT/10(6) nucleotides at the 10 microM plasma-equivalent AZT dose at P(1), P(5), and P(14), respectively. An exposure-related increase in the frequency of micronuclei (MN) was observed in cells exposed to either 10 or 800 microM AZT during P(1)-P(14). Analysis of the cell cycle profile revealed an accumulation of S-phase cells and a decrease in G(1)-phase cells during exposure to 800 microM AZT for 14 passages. When MOLT-3 cells were grown in A...Continue Reading

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Citations

Apr 6, 2013·The Journal of Infectious Diseases·Isabelle André-SchmutzStéphane Blanche
Jan 21, 2014·Environmental Toxicology and Pharmacology·Hugo Martins de OliveiraVanessa M Andrade
Mar 18, 2015·Bioorganic & Medicinal Chemistry·Kayla M BorlandVladislav A Litosh
Sep 14, 2018·Drug and Chemical Toxicology·Allyne Cristina GrandoRafael Rodrigues Dihl

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Methods Mentioned

BETA
flow cytometry
fluorescence-activated cell sorter

Software Mentioned

CellQuest
ModFit

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