Cardiac pathologic effects of azidothymidine (AZT) in Mg-deficient mice.
Treatment of HIV with AZT (zidovudine) may have toxic side effects as a result of multiple mechanisms. It is known that patients with AIDS may suffer from magnesium deficiency (MgD). We studied selected biochemical and histopathologic consequences of AZT administration (0.7 mg/mL in drinking water) with concurrent Mg-deficient (20% of normal) diet in male C57Bl/6N mice for 3 wk. Significant decreases in red blood cell glutathione (GSH) were evident in the Mg-deficient mice with or without AZT treatment, suggesting compromised antioxidant capacity in the blood. Although MgD alone led to a 1.9-fold increase in plasma thromboxane B(2) (TXB(2), derived from the highly vasoconstrictive TXA(2)), AZT + MgD increased the TXB(2) level 3.5-fold. AZT (+/-MgD) provoked prominent hepatic damage expressed by distortion of lobular architecture, nuclear and cellular swelling, and inflammatory lesions and loss of hepatocytes. AZT alone caused mild cardiac lesions, resulting in partial cardiac fibrosis, especially in the atrium. AZT + MgD caused only scattered small-size cardiac lesions consisting of microscopic foci of inflammatory infiltrates in the ventricles but led to more prominent lesions, fibrosis, and scars in the atrium. MgD or AZT alone caused varying degrees of skeletal muscle degeneration; in combination, more intense degeneration and regeneration of muscle cells were evident. In conclusion, it is suggested that both the decreased blood GSH and elevated plasma TXA(2) might contribute, at least in part, to the aggravated pathological damages observed in the atrium and skeletal muscle of the AZT-treated Mg-deficient mice.
Mak
I Tong
IT
Department of Biochemistry & Molecular Biology, Division of Experimental Medicine, The George Washington University Medical Center, Washington, DC, USA.
Goldfarb
Maya G
MG
Weglicki
William B
WB
Haudenschild
Christian C
CC
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D005978:Glutathione / Q000097:blood; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008275:Magnesium Deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D013929:Thromboxane B2 / Q000097:blood; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D015215:Zidovudine; D013929:Thromboxane B2; D005978:Glutathione