1,2-Dichlorobenzene-mediated hepatocellular oxidative stress in Fischer-344 and Sprague-Dawley rats.
1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 344 (F-344) rats but not in Sprague-Dawley (SD) rats. While Kupffer cell-dependent oxidative stress plays a role in the progression of 1,2-DCB-mediated liver injury, we hypothesize that initiation of liver injury is due to oxidative events within the hepatocyte. This study compared hepatocellular oxidative stress marked by glutathione disulfide (GSSG) and glutathione (GSH) production in either bile, liver, or isolated hepatocytes of F-344 and SD rats following 1,2-DCB administration. Hepatic GSH concentrations were depleted at a greater rate in F-344 than in SD rats within 12 h of 1,2-DCB administration (3.6 mmol/kg ip). In bile, GSSG concentrations were threefold greater in F-344 rats compared to SD rats by 9 h of 1,2-DCB treatment. Moreover, 1-aminobenzotriazole but not gadolinium chloride pretreatment blocked the rise in biliary GSSG concentrations following 1,2-DCB administration. In in vitro studies, isolated hepatocytes of F-344 rats had a 15% increase in cellular GSSG concentrations following 1 h of 1,2-DCB (3.55 nmol) exposure, while GSH decreased 22% by 6.5 h compared to controls. In contrast, isolated SD hepatocytes exposed to 1,2-DCB had no increase in GSSG and only an 8% reduction in GSH. Furthermore, parameters of lipid peroxidation were increased in F-344 rats and not in SD rats. Collectively, these data suggest that hepatocellular oxidative stress is dependent upon bioactivation and the enhanced oxidative stress in the F-344 rat may explain its susceptibility to 1,2-DCB compared to the SD rat.
Younis
H S
HS
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona 85721-2466, USA.
Hoglen
N C
NC
Kuester
R K
RK
Gunawardhana
L
L
Sipes
I G
IG
D000818:Animals; D001646:Bile / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D001944:Breath Tests; D002469:Cell Separation; D002722:Chlorobenzenes / Q000633:toxicity*; D004980:Ethane / Q000032:analysis; D005682:Gadolinium / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D019803:Glutathione Disulfide / Q000032:analysis / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D015415:Biomarkers; D002722:Chlorobenzenes; C004726:2-dichlorobenzene; D005682:Gadolinium; D005978:Glutathione; D004980:Ethane; C038958:gadolinium chloride; D019803:Glutathione Disulfide