AZT-induced oxidative cardiovascular toxicity: attenuation by Mg-supplementation.
Cardiovascular effects of chronic AZT treatment on SD male rats (185 g) fed either a normal Mg diet (0.1% MgO) or a high Mg diet (0.6% MgO) were examined. AZT treatment (1 mg/ml drinking water) for 3 weeks led to a 5.5-fold (0.88 +/- 0.11 nmol/min/10(6) cells, P < 0.05) elevation in neutrophil basal activity of O2(-) production versus controls (0.16 +/- 0.03 nmol/min, assayed ex vivo as SOD-inhibitable cytochrome c reduction). Concomitantly, plasma 8-isoprostane and PGE(2) levels rose 2.1-fold and 3-fold (both P < 0.05), respectively, compared to control; however, RBC GSH decreased 28% (P < 0.02) with GSSG content increased 3-fold, indicative of systemic oxidative stress. High Mg diet substantially attenuated the AZT-induced neutrophil activation by 70% (0.26 +/- 0.05 nmol/min, P < 0.05); reduced plasma 8-isoprostane and PGE(2) to levels comparable to normal; and RBC GSH was restored back to 92% of control. AZT alone caused moderate, but significant vascular inflammatory lesions in the heart (assessed by H&E staining). Immunohistochemical staining revealed significantly higher (about 4-fold) infiltration of CD11b positive cells (WBC surface marker) in the atria and ventricles of AZT-treated rats. However, these inflammatory pathological markers were minimal in samples of rats treated with AZT plus high Mg diet. Moreover, AZT alone significantly (P < 0.02) decreased rat weight gain by 21% at 3 weeks; Mg-supplementation completely prevented (P < 0.05) the weight gain loss due to AZT intake. It is concluded that high dietary Mg may provide beneficial effects against AZT toxicity due to its systemic antioxidative/anti-inflammatory properties.
Mak
I Tong
IT
Department of Biochemistry & Molecular Biology, Division of Experimental Medicine, The George Washington University Medical Center, 2300 Eye Street, N.W. Ross Hall, Rm 443, Washington, DC 20037, USA. itmak@gwu.edu
Chmielinska
Joanna J
JJ
Kramer
Jay H
JH
Weglicki
William B
WB
D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019587:Dietary Supplements; D008274:Magnesium / Q000008:administration & dosage*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015215:Zidovudine / Q000633:toxicity*
D015215:Zidovudine; D008274:Magnesium