Consequences of cadmium toxicity in rat hepatocytes: mitochondrial dysfunction and lipid peroxidation.
Cadmium (Cd) (10-100 microM) decreased the ATP/ADP ratio and enhanced lipid peroxidation (LPO) (measured as thiobarbituric acid reactants) in incubated rat hepatocytes. Analysis of the subcellular distribution of Cd indicated its preferential attachment to the inner membranes of mitochondria. Incubation of isolated mitochondria with 0.005-0.05 microM Cd resulted in increased formation of formazans from nitroblue tetrazolium salts, indicating enhanced membrane permeability to succinate. These Cd-concentrations also diminished mitochondrial ATP. LPO in mitochondria strongly increased only after Cd-exposures above 1 microM Cd. Similarly, in Cd-treated hepatocytes decreases in ATP/ADP ratios corresponded to increases in LPO stimulation only at 30 and 60 min but not at 15 min of incubation when ATP/ADP ratios were already affected. Moreover, neither hepatocellular ATP/ADP decrease nor mitochondrial formazan formation due to Cd were prevented by (+)-cyanidanol-3, an effective inhibitor of Cd-induced LPO. These data suggest that even low Cd-concentrations in the hepatocyte disturb the integrity of its mitochondrial membranes concomitantly impairing the hepatocellular energy supply. LPO, only observed at higher Cd-concentrations, is not responsible for these adverse Cd-effects.
D000244:Adenosine Diphosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002104:Cadmium / Q000009:adverse effects*; D005260:Female; D008054:Lipid Peroxides / Q000096:biosynthesis*; D008099:Liver / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D002104:Cadmium; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate