Copper impairs biliary epithelial cells and induces protein oxidation and oxidative DNA damage in the isolated perfused rat liver.
Copper is one of the major metals causing environmental contamination. Previous studies showed that copper induced toxic effects in isolated perfused rat liver models and these effects were associated with lipid peroxidation. Here we investigated whether effects of copper (at concentrations of 0.01, 0.03, and 0.1 mM of Cu(2+) in Krebs-Henseleit buffer perfusing the isolated rat liver for 60 min), were associated with biliary epithelial cell injury, as well as protein oxidation and oxidative DNA damage. The highest concentration of copper in perfusate (0.1 mM) did not allow complete evaluation of all parameters because it blocked portal flow within 30 min of perfusion, indicating severe microcirculatory disturbances. Further, copper decreased secretion of bile and it increased lactate dehydrogenase, aspartate transaminase, and alanine transaminase leakage into perfusate as well as liver weight in a dose-dependent manner. Biliary gamma-glutamyltransferase, an index of biliary epithelial cell integrity increased similarly at 0.01 and 0.03 mM copper concentrations in perfusate. Compared to controls, 0.01 and 0.03 mM concentrations of copper increased the amount of thiobarbituric acid reacting substances, a marker of lipid peroxidation, tissue protein carbonyl groups, an index of protein oxidation, and 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative DNA damage. The results suggest that toxic effects of copper in the isolated perfused rat liver may involve biliary epithelial cells and they are associated with lipid peroxidation, protein oxidation, and oxidative DNA damage.
Alexandrova
Albena
A
Laboratory of Free Radical Processes, Institute of Physiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria. a_alexandrova_bas@yahoo.com
Kebis
Anton
A
Misl'anová
Csilla
C
Kukan
Marián
M
D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D001646:Bile / Q000187:drug effects; D001659:Biliary Tract / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003300:Copper / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000187:drug effects
D011506:Proteins; D003300:Copper; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase