Genotoxicity and mitochondrial damage in human lymphocytic cells chronically exposed to 3'-azido-2',3'-dideoxythymidine.
AZT (3'-azido-2',3'-dideoxythymidine), the first nucleoside analog approved for the treatment of AIDS (acquired immunodeficiency syndrome), induces significant toxic effects in humans exposed to therapeutic doses. As an inhibitor of the HIV-1 (human immunodeficiency virus 1) reverse transcriptase, AZT blocks the incorporation of nucleotides into the host's newly synthesized DNA. Incorporation of AZT into mammalian DNA as well as specific localization of the drug into telomeric DNA, has been previously documented by immunohistochemistry. As with other nucleoside analogs, AZT has affinity for polymerase-gamma, the enzyme responsible for the replication of mitochondrial DNA. In order to examine the mechanisms of toxic events induced by long-term AZT exposure, human T-lymphocytic H9 cells were cultured with 25 microM AZT for 7 months. In the resulting H9-AZT cells, incorporation of AZT into DNA was demonstrated by radioimmunoassay and immunohistochemistry, chromosomal aberrations and micronuclei were scored and intracellular lipid distribution was determined. Two pmol of AZT per microgram of DNA were detected by radioimmunoassay in H9-AZT cells. Control cells showed negative values in the radioimmunoassay. Cytogenetic observations on H9-AZT cells showed an increase in chromosomal aberrations and nuclear fragmentation when compared with unexposed H9 cells. Electron microscopy revealed mitochondrial damage and an elevated accumulation of neutral intracellular lipid deposits probably as a consequence of a distortion in the beta-oxidation of fatty acids normally carried out by this organelle. The toxicities explored here suggest that the mechanisms of AZT induced cytotoxicity in bone marrow of the patients chronically exposed to the drug in vivo may involve both chromosomal and mitochondrial DNA damage.
Agarwal
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RP
Medical Oncology, University of Miami School of Medicine, FL 33136, USA.
Olivero
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OA
D019380:Anti-HIV Agents / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D018736:DNA Adducts / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009152:Mutagenicity Tests; D011863:Radioimmunoassay; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D018736:DNA Adducts; D004272:DNA, Mitochondrial; D019344:Lactic Acid; D015215:Zidovudine