Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice

Abstract

The hepatotoxicity of several drugs is increased by mild viral infections. During such infections, death receptor ligands are expressed at low levels, and most parenchymal cells survive. We tested the hypothesis that subliminal death receptor stimulation may aggravate the hepatotoxicity of drugs, which are transformed by cytochrome P-450 cytochrome P-450 into glutathione-depleting reactive metabolites. Twenty-four-hour-fasted mice were pretreated with a subtoxic dose of the agonistic Jo2 anti-Fas antibody (1 g per mouse) 3 hours before acetaminophen (500 mg/kg) or 1 hour before bromobenzene (400 mg/kg) administration. Administration of Jo2 alone increased hepatic inducible nitric oxide synthase nitric oxide synthase but did not modify serum alanine aminotransferase (ALT), hepatic adenosine triphosphate (ATP), glutathione (GSH), cytochrome P-450, cytosolic cytochrome c, caspase-3 activity or hepatic morphology. However, pretreating mice with Jo2 further decreased both hepatic GSH and ATP by 40% 4 hours after acetaminophen administration, and further increased serum ALT and the area of centrilobular necrosis at 24 hours. In mice pretreated with the Jo2 antibody before bromobenzene administration, hepatic GSH 4 hours after bromobenzene administration was 51% lower than in mice treated with bromobenzene alone, and serum ALT activity at 24 hours was 47-fold higher. In conclusion, administration of a subtoxic dose of an agonistic anti-Fas antibody before acetaminophen or bromobenzene increases metabolite-mediated GSH depletion and hepatotoxicity. Subliminal death receptor stimulation may be one mechanism whereby mild viral infections can increase druginduced toxicity. (HEPATOLOGY 2004;39:655-666.)

Role of mammalian cytosolic molybdenum Fe–S flavin hydroxylases in hepatic injury

“…While CCl 4 , CHCl 3 and TAA represent classic models where free radicals are the direct cause of hepatic injury (Beddowes et al, 2003;Jin et al, 2005;Manna et al, 2006;Sehrawat and Sultana, 2006;Pallottini et al, 2006;Ito et al, 2007;Raja et al, 2007), BB and AAP produce oxidative stress by depleting glutathione (GSH); BB and AAP are metabolized into the electrophilic products that readily conjugate with GSH (Delnomdedieu et al, 1998;Tinel et al, 2004;Hsu et al, 2006;Sener et al, 2006). Irrespective of the mechanism, oxidative stress is involved in the liver injury by either of the hepatotoxin used in this study.…”

Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice

“…After 16-hour fasting (for maximal CYP2E1 induction), mice were administered intraperitoneally with Sal or with agonistic Jo2 hamster anti-mouse Fas monoclonal antibody (BD Pharmingen, San Diego, CA), 0.2 g/g body weight. 20 A Jo2 concentration of 0.2 g per gram body weight or about 4 g per mouse was found to initiate mild toxicity, so this was the dose of Jo2 chosen for the subsequent experiments.…”

Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

“…Hepatotoxicity driven by acetaminophen (APAP) overdose is the most common cause of death by acute liver failure in patients upon hospitalization (44)(45)(46)(47). Fas signaling plays a key role in this clinical setting (48)(49)(50). We therefore investigated the hepatoprotective potential of ADAM17 in wild-type mice treated with a lethal dose of APAP (600 mg/kg, i.p.).…”