Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo (original) (raw)
Related papers
Drug-induced lipid peroxidation in mice—II
Biochemical Pharmacology, 1982
If injected intravenously 2 hr before the drug, a dose of more than 175 mg/kg body weight glutathione (0.57 mmo~/kg) protected male mice from acute liver necrosis induced by intraperitoneal administration of 400 mg/kg (2.65 mmol/kg) paracetamol. Soluble glutathione yielded a limited, and liposomally entrapped glutathione an optimal dose-dependent protective effect against drug-induced lipid peroxidation (as measured by in vivo ethane exhalation) liver necrosis (assessed by serum transaminases) and hepatic glutathione depletion (determined post mortem). N-Acetylcysteine solution had no effect in this model.
Role of Lipid Peroxidation as a Mechanism of Liver Injury after Acetaminophen Overdose in Mice
Toxicological Sciences, 2003
Mitochondrial oxidant stress and peroxynitrite formation have been implicated in the pathophysiology of acetaminophen-induced (AAP-induced) liver injury. Therefore, we tested the hypothesis that lipid peroxidation (LPO) might be involved in the injury mechanism. Male C3Heb/FeJ mice fed a diet high in vitamin E (1 g d-␣-tocopheryl acetate/kg diet) for 1 week had 6.7-fold higher hepatic tocopherol levels than animals on the control diet (8.2 ؎ 0.1 nmol/g liver). Treatment of fasted mice with 300 mg/kg AAP caused centrilobular necrosis with high plasma alanine aminotransferase (ALT) activities at 6 h (3280 ؎ 570 U/l) but no evidence of LPO (hepatic malondialdehyde, 4-hydroxynonenal). Animals on the vitamin E diet had similar injury and LPO as mice on the control diet. To verify a potential effect of the vitamin E diet on drug-induced liver injury, animals were pretreated with a combination of phorone, FeSO 4 , and allyl alcohol. We observed, 2 h after allyl alcohol, massive LPO and liver cell injury in the livers of animals on the control diet, as indicated by a 32-fold increase in malondialdehyde levels, extensive staining for 4-hydroxynonenal, and ALT activities of 2310 ؎ 340 U/l. Animals on the vitamin E diet had 40% lower hepatic malondialdehyde levels and 85% lower ALT values. Similar results were obtained when animals were treated for 3 days with ␣or ␥-tocopherol (0.19 mmol/kg, ip). Both treatments reduced LPO and injury after allyl alcohol but had no effect on AAP hepatotoxicity. Thus, despite the previously shown mitochondrial oxidant stress and peroxynitrite formation, LPO does not appear to be a critical event in AAPinduced hepatotoxicity.
1989
The role of the glutathione peroxidase/reductase (GSH-Px/GSSG-Rd) enzyme system in protection from paracetamol toxicity was investigated in isolated mouse hepatocytes in primary culture. The effect of inhibitors of these enzymes on the toxicity of paracetamol and on t-butylhydroperoxide (r-BOOH), used as a positive control, was determined. 1,3-Bis(chloroethyl)-1-nitrosourea (BCNU) was used to inhibit GSSG-Rd, and goldthioglucose (GTG) used to inhibit GSH-Px. Both these inhibitors increased cell membrane damage in response to oxidative stress initiated by t-BOOH. However, they also increased the susceptibility of hepatocytes to paracetarnol toxicity, indicating that a component of paracetamol's toxic effect involves formation of species that are detoxified by the GSH-Px/GSSG-Rd enzymes. To further examine the role of these enzymes, age-related differences in their activity were exploited. Hepatocytes from two-week-old mice were less susceptible to both j-BOOH and paracetamol toxicity than were those from adult mice. This corresponds to higher activity of cytosolic GSH-Px/ GSSG-Rd in this age group. However, after inhibition of GSSG-Rd with BCNU, hepatocytes from these postnatal mice were more susceptible to paracetamol toxicity. This suggests that the higher activity of GSH-Px/GSSG-Rd in hepatocytes from two-week-old mice is responsible for their reduced susceptibility to paracetamol toxicity. The data indicate that the GSH-Px/GSSG-Rd enzymes contribute to protection from paracetamol toxicity and suggest that formation of peroxides contributes to this drug's hepatotoxic effects.
Drug-induced lipid peroxidation in mice—III
Biochemical Pharmacology, 1982
The half-life of extracellular glutathione was found to be 1.9 min in fed mice with a hepatic glutathione content of 44-+ 10 nmol glutathione per mg protein. It was 4.9 min in animals that had been fed for 48 hr a liquid sucrose diet resulting in a decreased hepatic glutathione of 25-+ 7 nmol/mg. A single intravenous injection of 16.2 #mol liposomally entrapped glutathione led to an increase in hepatic glutathione to 45 nmol/mg in the sucrose-fed mice after 2 hr and had no effect in the fed group. The spleen glutathione content reached a maximum at 30 min after injection in both groups. The maximum uptake into liver was 21% of the applied dose, into the spleen 7% and into the kidneys 2.4%. Injection of glutathione in solution led to a similar increase of hepatic glutathione as observed with GSHcontaining liposomes, while liposomes filled with the constituent amino acids had only a marginal effect. The spleen took up only liposomal GSH. In contrast, the kidney glutathione content increased within 10 min up to 150% upon injection of free glutathione. The findings are consistent with a rapid hydrolysis of extracellular free glutathione followed by an interorgan turnover utilizing the constituent amino acids for resynthesis in the liver. Pretreatment of the animals with the glutathione synthesis inhibitor buthionine sulfoximine essentially abolished the hepatic glutathione increase upon treatment with GSH-liposomes or with the free compound. The finding that only liposomally entrapped glutathione protects mice against liver necrosis induced by highly dosed paracetamol is discussed with respect to differential uptake and distribution of GSH-liposomes in the liver.
Toxicology, 1985
A primary culture system of postnatal rat hepatocytes was utilized to study the cytotoxicity of acetaminophen and the toxicological significance of giutathione (GSH) depletion. The relative time of onset and magnitude of GSH depletion, lipid peroxidation and cytotoxicity were contrasted in order to gain insight into their interrelationships. Exposure of the hepatocytes to acetaminophen resulted in time-and dose<lependent depletion of cellular GSH. The acetaminophen-induced GSH depletion and ensuing lactate dehydrogenase (LDH) leakage were quite modest and delayed in onset, in contrast to that caused by iodoacetamide (IAA) and by diethylmaleate (DEM), 2 well-known depletors of GSH. There was comparable LDH leakage, irrespective of drug treatment, when GSH levels decreased to about 20% of normal. Reduction of GSH levels below the 20% threshold by IAA treatment resulted in marked LDH leakage and loss of viability. Maximal LDH leakage in response to IAA and acetaminophen preceded maximal malondialdehyde (MDA) formation, suggesting that lipid peroxidation may be a consequence of cell damage as well as GSH depletion. IAA and DEM produced a comparable, modest accumulation of MDA, yet IAA was much 127 more cytotoxic. These findings indicate that lipid peroxidation does not play a central role in hepatocellular injury by compounds which deplete GSH, although it may contribute to degeneration of the cell. As events in the cultured postnatal hepatocytes paralleled those reported in vivo, the system can be a useful and valid model with which to study mechanisms of chemical toxicity.
Journal of Bioequivalence & Bioavailability
Background: Our aim was to investigate the effect of intra-oesophageal acetaminophen instillation on the selected antioxidative enzymes activity: superoxide dismutase isoenzymes (MnSOD, Cu/ZnSOD), glutathione peroxidase (GPX), glutathione-S-transferase (GST), glutathione reductase (GR) and lipid peroxidation in rat liver after 4, 8 and 12 weeks of exposure. Material and methods: Male Wistar FL strain rats weighing 150-160 g were treated with paracetamol by intraoesophageal instillation at a dose of 2.4 g/kg b.w every day up to 12 weeks. During the whole experiment rats were kept in a night-and-day’s cycle lasting twelve hours, with standard feed ad libitum. Rats were sacrificed after 4, 8 and 12 weeks of the study. The collected tissue liver was homogenized and the above mentioned enzymes were determined in the supernatants. Results: The current study revealed the presence of paracetamol-induced changes in the activities of antioxidative enzymes in comparison to the control values. ...
T Ransferases in Pro Tec Tion Agains T Acetaminophen-Induced Lipid Peroxidation in Weanling Rats
2013
Resistance of the weanling rat to acetaminophen (AP AP)-induced hepatotoxicity is manifested with regard to a surge in APAP-glutathione (OSH) conjugate formation in the liver [Allameh et al. Mech Aging Dev 95(1997)71]. The present study was conducted to assess the role of this detoxification pathway in APAP induced lipid per6xidationin the liver. Lipid peroxidation measured as thiobarbituric acid reactive substances (,fBARS) in rat liver homogenate was observed to be increased due to a decrease in hepatic cellular GSH concentration. Cellular GSH content was relatively lower in growing liver and further decreased in rats treated with either GSH-depleting agents or APAP, whereas adult animals under APAP treatment suffered significantly less depletion of GSH. AP AP injection to weanling rats pre-treated with diethylmaleate (DEM) aggravated lipid peroxidation. Administration of a single large dose of AP AP (500 mg/kg b. w.) to weanling rats, 3 h before sacrifice, which caused 46% GSH d...
Drug-induced lipid peroxidation in mice—IV
Biochemical Pharmacology, 1983
A method is described to measure in vitro lipid peroxidation by the hydrocarbon evolution technique in cell homogenates or subcellular suspensions of mouse liver. The drug acetaminophen (paracetamol) was shown to quench Fe/ADP-induced as well as NADPH-induced microsomal lipid peroxidation. The pH dependence of ethoxycoumarin deethylation, NADPH-cytochrome P-450 or NADH-cytochrome b5 reductase activities, and of NADPH-induced microsomal H202 formation in the presence or absence of acetaminophen was investigated. The presence of the drug at I mmole/1 caused a shift.of the NADPH-or the (NADPH + NADH)-supported H202 formation to a more alkaline pH. Both processes were inhibited by monooxygenase inhibitors. The dependence of microsomal parameters on the NADP/NADPH ratio was studied and related to the profile of the superoxide dismutase sensitive adrenochrome formation or H202 formation in the presence and absence of acetaminophen. With a maximum at an NADPfNADPH ratio of 100 a microsomal H202 production of 5 nmoles/mg protei~ rain without a concomitant adrenochrome formation was observed only in the presence of acetaminophen. At a NADP/NADPH ratio of 0.01, 8 nmoles/mg/min H202 and 16 nmoles/mg/min adrenochrome were formed in the absence of acetaminophen. In the presence of 1 mmole/l of the drug, this was quenched to 7 nmoles/mg/min H202 and 13.5 nmoles/mg/min adrenochrome, respectively. The steady state of the oxy-cytochrome P-450 complex paralleled H202 formation in the absence of acetaminophen, while it did not so in the presence of it. In further experiments the isocitrate dehydrogenase activity was used to modulate the pyridine nucleotide redox potential: H202 formation as well as ethane evolution was dissociated into two phases where acetaminophen acted antioxidatively if the pyridine nucleotide couple was reduced. The in vitro covalent binding of the drug paralleled H202 formation as well as ethane evolution. These observations seem to be of general importance with respect to oppositely directed effects of drugs in vitro and in vivo. Possible mechanisms relating H202 production, ethane evolution and protein binding to a common radical intermediate are discussed.