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ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg135
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received February 3, 2003; accepted April 24, 2003
© 2003 Society of Toxicology

In Vitro Toxicology and Alternative Testing

Pyruvate Attenuates Myoglobin in Vitro Toxicity

Monica A. Valentovic 1* Jennifer Minigh 1

1 Department of Pharmacology, Marshall University School of Medicine, 1542 Spring Valley Drive, Huntington, WV 25704-9388

* To whom correspondence should be addressed. E-mail: Valentov{at}marshall.edu.


  Abstract

Myoglobinuria is a complication of crush injury as well as substance abuse. This study examined whether pyruvate modified myoglobin in vitro renal toxicity. Renal slices from Fischer 344 rats were incubated for 120 min with 0-12 mg/ml myoglobn. In an initial study, gluconeogenesis was stimulated by the addition of 10 mM pyruvate during the final 30 min. In all other studies, renal slices were incubated with myoglobin in the presence of 0 or 10 mM pyruvate for 120 min. Myoglobin increased lactate dehydrogenase (LDH) release and this was not modified by the presence of pyruvate for the last 30 min of the incubation. Myoglobin toxicity was reduced by coincubation of myoglobin with pyruvate for 120 min. LDH leakage was increased 1.2, 1.7 and 1.8 fold above control by 4, 10 and 12 mg/ml myoglobin, compared to 1.2, 1.3 and 1.3 fold in slices co-incubated with 10 mM pyruvate, respectively. Myoglobin diminished ATP levels but pyruvate maintained a 5 time higher level of ATP within the slices. Glucose (10 mM) provided protection only for the low concentration (4 mg/ml) of myoglobin. Myoglobin induced oxidative stress while pyruvate prevented the rise in lipid peroxidation and glutathione disulfides by myoglobin. Myoglobin diminished total glutathione levels in pyruvate treated tissue but glutathione levels remained higher than tissues incubated in the absence of pyruvate. These results indicate that pyruvate reduced toxicity by preventing oxidative stress and via supply of an energy substrate.


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