Strain difference (WKY, SPRD) in the hepatic antioxidant status in rat and effect of hypertension (SHR, DOCA). Ex vivo and in vitro data.
We assessed the hepatic antioxidant status of spontaneously (SHR) and desoxicorticosterone acetate (DOCA)-induced hypertensive rats and that of respective normotensive Wistar Kyoto (WKY) and Sprague-Dawley (SPRD) rats. For this we evaluated, ex vivo in liver cytosols, reduced glutathione (GSH) content, glutathione-related enzyme (peroxidase, reductase and transferase) activities as well as the rate of lipid peroxidation in 9-11 week-old rats. The antioxidant status and the cytotoxicity of acetaminophen, a radical- and hydrogen peroxide-mediated hepatotoxic compound, were also assessed in vitro in cultured hepatocytes isolated from hypertensive (SHR, DOCA) and normotensive control (WKY, SPRD) rats. Our results suggest that a difference exists in the hepatic antioxidant status between rat strains, with GSH levels being lower (-15%) and lipid peroxidation rate higher (+30%) in WKY compared to SPRD rats. In hepatocyte cultures from WKY rats, both GSH content and catalase activity were lower (-30 and -70% respectively) compared to hepatocyte cultures from SPRD rats. This was associated with a 35% higher cytotoxicity of acetaminophen in cultured hepatocytes from WKY rats compared to that in hepatocytes from SPRD rats. Hypertension in DOCA rats (mmHg: 221+/-9 vs. 138+/-5 in control SPRD rats) was associated with decreases (about 30%) in both glutathione peroxidase (GSH-Px) and catalase activities, ex vivo in livers and in vitro in hepatocyte cultures. Hypertension in SHR (mmHg: 189+/-7 vs. 130+/-5 in control WKY rats) was also associated with decreases (about 50%) in GSH-Px activity, ex vivo in livers and in vitro in hepatocyte cultures but catalase activity was not modified. The IC50 of acetaminophen was also lower in hepatocytes from hypertensive rats compared to respective controls, which could be related to the weakened antioxidant status in hepatocytes from hypertensive rats. Our data thus suggest that hepatocyte cultures are appropriated tools in which to assess hepatotoxicity and hepatoprotection in hypertension.
Binda
D
D
Laboratoire de Biologie Cellulaire, UFR Médecine-Pharmacie, Besançon, France.
Nicod
L
L
Viollon-Abadie
C
C
Rodriguez
S
S
Berthelot
A
A
Coassolo
P
P
Richert
L
L
D000082:Acetaminophen / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D017392:Thiobarbituric Acid Reactive Substances; D000082:Acetaminophen; D003900:Desoxycorticosterone; D002374:Catalase; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione