Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production.
Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 microM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45-) cell proliferation was 2.5 microM (SD+/-0.7) and 0.023 microM (SD+/-0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD+/-23) at 10 microM AZT and in erythroid-rich cultures it increased by 134% (SD+/-24) in the presence of 0.5 microM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 microM, whereas in erythroid rich cultures this AZT IC50 was < 0.0005 microM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.
Lewis
L D
LD
Department of Medicine and Pharmacology and Molecular Sciences (Division of Clinical Pharmacology), The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Lionel.D.Lewis@Dartmouth.edu
Amin
S
S
Civin
C I
CI
Lietman
P S
PS
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D018952:Antigens, CD34 / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D019344:Lactic Acid / Q000096:biosynthesis*; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity*
D019380:Anti-HIV Agents; D018952:Antigens, CD34; D004272:DNA, Mitochondrial; D019344:Lactic Acid; D015215:Zidovudine