The human immunodeficiency virus type 1 Tat protein potentiates zidovudine-induced cellular toxicity in transgenic mice.
3'-Azido-2',3'-dideoxythymidine (AZT, zidovudine) is the principal antiretroviral agent in the treatment of AIDS. Although beneficial, AZT remains restricted for human usage because of its severe toxic effects. We examined the AZT sensitivity in transgenic mice expressing HIV-1 one-exon-encoded 72 amino acid Tat (Tat72) and full-length 86 amino acid Tat (Tat86) proteins. Administration of AZT (1 mg/ml) in drinking water for 1 week resulted in a three- to fourfold decrease in hematopoietic progenitors from bone marrow in Tat mice compared to AZT-treated nontransgenic controls as determined by erythroid and granulocyte/macrophage colony-forming unit assays. In liver and thymus, two of the tissues examined, AZT treatment of Tat mice resulted in as much as 80-90% suppression of Mn-superoxide dismutase (Mn-SOD) activity. Other parameters associated with loss of Mn-SOD such as increase in carbonyl proteins and decrease of sulfhydryl content were also significantly enhanced by AZT in Tat mice. Our in vivo study suggests that AZT therapy is associated with oxidative damage affecting cellular functions in several tissues and that Tat is one of the contributory factors in AZT-induced toxicities. The findings of AZT-induced oxidative damage may help to improve the therapeutic index of AZT and other related drugs in AIDS patients.
Prakash
O
O
Laboratory of Molecular Oncology, Alton Ochsner Medical Foundation, New Orleans, Louisiana 70121, USA.
Teng
S
S
Ali
M
M
Zhu
X
X
Coleman
R
R
Dabdoub
R A
RA
Chambers
R
R
Aw
T Y
TY
Flores
S C
SC
Joshi
B H
BH
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000473:pathology; D005091:Exons; D015696:Gene Products, tat / Q000096:biosynthesis*; D015756:Genes, tat; D015497:HIV-1 / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism*; D013950:Thymus Gland / Q000201:enzymology; D015215:Zidovudine / Q000633:toxicity*; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D015215:Zidovudine; D013482:Superoxide Dismutase