Journal
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A
Volume 63, Issue 3, Pages 221-235Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/15287390151101583
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Funding
- NIEHS NIH HHS [ES 03187] Funding Source: Medline
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A bolus dose of cadmium metallothionein (CdMT) produces renal proximal tubular dysfunction because it accumulates in the tubular epithelial cells and undergoes rapid degradation, releasing Cd. Morphologically, mitochondria appear to be the target organelle. The present study examined changes in renal cortical mitochondrial function following CdMT administration and investigated whether some of these effects could be ascribed to Cd2+ accumulation in the mitochondria. Sprague-Dawley rats were injected ip with 0.3 mg Cd as CdMT/kg and the animals were sacrificed after 6, 8, or 12 h. Two- to threefold increases in urinary protein excretion and LDH activity were evident at 8 h, with marked elevations (11- and 29-fold) thereafter. Renal cortical mitochondria were swollen and rounded at IZ h. The mitochondrial Cd level was 399 pmol/mg protein at 6 h and did not change significantly during the next 6 h: however, mitochondrial respiratory function declined with time. At 12 h, state 3 oxygen consumption, respiratory control ratio (RCR), and ADP:O (P/O) ratio were 48, 49, and 76% of control values, respectively, indicating inhibition of electron transfer and oxidative phosphorylation. The direct effect of Cd on mitochondrial function was examined by incubating mitochondria from untreated rats with 0.1-2 muM CdCl2. Rapid uptake of Cd resulted in concentration-dependent effects on respiration. After 1 min of incubation with 2 muM Cd, the mitochondria contained 262 mu gCd/mg protein and state 3 respiration and RCR values were 75 and 33% of control levels, respectively Thus, renal proximal tubular cell damage following a bolus dose of CdMT involves perturbations in mitochondrial respiration, brought on by the accumulation of Cd.
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