Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model.
To examine the mechanism of mitochondrial myocytotoxicity caused by long-term administration of zidovudine (AZT) in human immunodeficiency virus-positive patients, we examined the effect of AZT in vitro on human muscle in tissue culture and in vivo in rats treated with daily intraperitoneal injections of AZT at doses equivalent to the total daily dose used in acquired immunodeficiency syndrome patients. After 19 days, the AZT-treated myotubes in tissue culture exhibited abnormal mitochondria characterized by proliferation (mean +/- SD, 27.5 +/- 8 mitochondria/16 microns2 surface area, compared with 12.8 +/- 4 in the control cultures (p less than 0.001], enlarged size, abnormal cristae and electron-dense deposits in their matrix. The changes were partially reversible after AZT withdrawal. Rats treated with AZT developed weight loss, 100-fold elevation of creatine kinase, and increased serum lactate and glucose. In tissues, AZT had its highest concentration in the skeletal muscle and the heart. Skeletal and heart muscles from the treated animals, but not the controls, showed enlarged mitochondria with disorganized or absent cristae and electron-dense deposits in their matrix. Study of the mitochondrial functions assessed by evaluating stimulated oxygen consumption rate, enzymatic activities of electron transport chain and coupling state of oxidative phosphorylation (respiratory control ratio) revealed a decrease in rotenone-sensitive NADH cytochrome C reductase (complex I + III) and an uncoupling effect demonstrated by decreased respiratory control ratio. We conclude that AZT, a DNA chain terminator, is a muscle mitochondrial toxin that affects the oxidation-phosphorylation coupling and the activity of complex I and III of the mitochondrial respiratory chain.
Lamperth
L
L
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Dalakas
M C
MC
Dagani
F
F
Anderson
J
J
Ferrari
R
R
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000818:Animals; D046508:Culture Techniques; D006801:Humans; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000648:ultrastructure; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D015215:Zidovudine / Q000633:toxicity*
D015215:Zidovudine