Marked interanimal differences in susceptibility of Sprague-Dawley rats to diquat-induced oxidative stress in the liver: correlation with hepatic uptake of diquat.
Biliary excretion of oxidized glutathione (GSSG) is used as an index of oxidative stress. We observed a marked interanimal difference in susceptibility to diquat-induced oxidative stress. When diquat injections (120 mumol/kg, i.v.) were administered to rats, a 60-fold increase in the biliary excretion of GSSG was observed in 40% of the rats (responders); however, diquat failed to increase the biliary excretion of GSSG in 60% of the animals (nonresponders). This interanimal variation is not due to differences in the hepatic metabolism or hepatobiliary transport of GSSG, as no interanimal difference was observed in the biliary output of GSSG after administration of another oxidative stress-inducing agent, t-butyl hydroperoxide (1.4 mmol/kg, i.v.). We then examined the hepatobiliary disposition of diquat (120 mumol/kg, i.v.) using a high-performance liquid chromatography procedure to quantitate diquat in blood, liver and bile. No differences in blood or biliary concentration of diquat were noted between responders and nonresponders. However, a marked difference was observed in the hepatic concentration of diquat in responders and nonresponders. The responders exhibited a 4-fold higher hepatic diquat concentration than the nonresponders (65 or 15 nmol/g, respectively) 30 min after diquat administration. In conclusion, this study demonstrates a marked interanimal variation in the susceptibility of Sprague-Dawley rats to oxidative stress produced by diquat, which appears to be due to interanimal difference in the hepatic accumulation of diquat.
Madhu
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C
Environmental Health and Occupational Medicine Center, University of Kansas Medical Center, Kansas City.
Gregus
Z
Z
Klaassen
C D
CD
D000818:Animals; D001646:Bile / Q000378:metabolism; D004178:Diquat / Q000493:pharmacokinetics / Q000633:toxicity*; D004220:Disulfides / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010545:Peroxides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020122:tert-Butylhydroperoxide
D004220:Disulfides; D010545:Peroxides; D020122:tert-Butylhydroperoxide; D004178:Diquat; D005978:Glutathione