Serum enzyme activities and hepatic triglyceride levels in acute and subacute acetaminophen-treated rats

A B S T R A C T Paraquat and diquat facilitate formation of superoxide anion in biological systems, and lipid peroxidation has been postulated to be their mechanism of toxicity. Paraquat has been shown to be more toxic to selenium-deficient mice than to controls, presumably as the result of decreased activity of the selenoenzyme glutathione peroxidase. The present study was designed to measure lipid peroxidation and to assess toxicity in control and selenium-deficient rats given paraquat and diquat. Lipid peroxidation was measured by determining ethane production rates of intact animals; toxicity was assessed by survival and by histological and serum enzyme evidence of liver and kidney necrosis. Paraquat and diquat were both much more toxic to selenium-deficient rats than to control rats. Diquat (19.5 umol/kg) caused rapid and massive liver and kidney necrosis and very high ethane production rates in selenium-deficient rats. The effect of paraquat (78 ,umol/kg) was similar to that of diquat but was not as severe. Acutely lethal doses of paraquat (390 ,umol/kg) and diquat (230 ,umol/kg) in control rats caused very little ethane production and no evidence of liver necrosis. These findings suggest that paraquat and diquat exert their acute toxicity largely through lipid peroxidation in selenium-deficient rats. Selenium deficiency had no effect on superoxide dismutase activity in erythrocytes or in 105,000 g supernate of liver or kidney. Glutathione peroxidase, which represents the only well-characterized biochemical function of selenium in animals, was dissociated from the protective effect of selenium against diquat-induced lipid peroxi-

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“…For compparison, admiiinistration of carbon tetrachloridle (24,25); such a rise occurred by 90 min after diquat (Fig. 1).…”

Section: Discussionmentioning

confidence: 93%

Liver Necrosis and Lipid Peroxidation in the Rat as the Result of Paraquat and Diquat Administration

Burk¹,

Lawrence²,

Lane³

1980

J. Clin. Invest.

265

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“…Acetaminophen has been associated with hepatocellular necrosis, ␣-naphthylisocyanate (ANIT) with intrahepatic cholestasis, and phenobarbital and Wy-14, 643 with hepatomegaly via hypertrophy or cell proliferation (2)(3)(4)(5). Each study incorporated time points corresponding to early and fulminant toxicity expectations and a third time point for recovery or restoration.…”

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confidence: 99%

Use of Proteomic Methods to Identify Serum Biomarkers Associated with Rat Liver Toxicity or Hypertrophy

Amacher¹,

Adler²,

Herath

et al. 2005

Clinical Chemistry

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Background: Our objectives were to identify serum marker proteins in rats that might serve as sensitive indicators of hepatomegaly, hepatocellular necrosis, or hepatobiliary injury and to use them to analyze data from a collaborative proteomics project. Methods: In each of 4 studies comprising the collaborative project, rats were given 1 of 4 compounds that target the liver through different mechanisms. Sera and liver samples were collected by terminal bleeds at 1 of 3 postdose time points. Sera were depleted of major secretory proteins and then separated into protein features by 2-dimensional gel electrophoresis (2DGE). Liver specimens were also processed and subjected to 2DGE. Protein spots that significantly increased or decreased in quantity after drug treatment were recovered, digested, analyzed by mass spectroscopy, and compared with available databases for identification. Criteria for further consideration were (a) temporal expression (i.e., increase or decrease at early, fulminant, or recovery periods), (b) known biological function, (c) probable hepatic origin, and (d) any previous association with toxicity in published studies. Markers that changed significantly at the early time point were important because of their potential sensitivity for signaling minimal damage. Results: Vitamin D-binding protein, paraoxonase, cellular retinol-binding protein, malate dehydrogenase, F-protein, and purine nucleoside phosphorylase were

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“…The nutritional state of patients has been identified as one of the risk factors of the APAP-induced hepatotoxicity (Amar and Schiff, 2007) and starvation appears to worsen APAP-induced hepatotoxicity after repeated dosing of APAP even at low dose levels (Eriksson et al, 1992). Hepatic glutathione, which detoxifies an APAP-derived reactive metabolite, NAPQI, is synthesized from several amino acids and undernourishment caused by starvation is considered to lower glutathione stores in the liver through decreased glutathione synthesis due to a low intake of proteins (Buttar et al, 1976).…”

Section: Introductionmentioning

confidence: 99%

“…Laboratory rodents differ from humans in many ways, including smaller genetic heterogeneity and narrower variation in diet and lifestyle. Further, intact rats more easily adapt to drugs including APAP than humans (O'Brien et al, 2000;Buttar et al, 1976Buttar et al, , 1977Strubelt et al, 1979;Poulsen and Thomsen, 1988;Shayiq et al, 1999). Thus, we employed daytime restricted fed (RF) rats as a modified-nutritional state model for human responders to APAP-induced hepatotoxicity because daytime-RF rats are well known to show some characteristic adaptive changes in energy metabolism, glucose synthesis and fatty acid oxidation associated with a shift of the animal's circadian rhythms (Baez-Ruiz et al, 2005;Leveille and Chakrabarty, 1968;Satoh et al, 2006;Wu et al, 2008) and to show acceleration of hepatic gluconeogenesis under restricted feeding conditions (Kobayashi et al, 2011) .…”

Section: Introductionmentioning

confidence: 99%

Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

et al. 2012

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Drug-induced Liver Injury (DILI) is becoming a significant public health issue because of its potential impact, not only on patients but also on the development of new drugs. DILI events are also the main cause of regulatory action pertaining to drugs, including denial of marketing approval, restrictions with respect to clinical indications and withdrawal from the marketplace (Lee, 2003;Smith and Schmid, 2006). Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent for relief of mild and moderate pain and is available as an over-the-counter medication. Overdoses of APAP, however, cause severe acute hepatotoxicity both in animals (Lauterburg et al., 1983) and humans (Black, 1984;Davidson and Eastham, 1966;Thomson and Prescott, 1966;Schiødt et al., 1997). APAP at therapeutic doses is rapidly metabolized in the liver principally through glucuronidation and sulfation, and only a small portion is oxidized by cytochrome P-450 2E1 to generate a highly reactive and cytotoxic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI), which is quickly conjugated by hepatic glutathione to yield a harmless water-soluble product, mercapturic acid (Lee et ABSTRACT -Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500 mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500 mg/kg and hepatic function parameters were increased at 300 and 500 mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

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Serum enzyme activities and hepatic triglyceride levels in acute and subacute acetaminophen-treated rats

Cited by 28 publications

References 14 publications

Liver Necrosis and Lipid Peroxidation in the Rat as the Result of Paraquat and Diquat Administration

Liver Necrosis and Lipid Peroxidation in the Rat as the Result of Paraquat and Diquat Administration

Use of Proteomic Methods to Identify Serum Biomarkers Associated with Rat Liver Toxicity or Hypertrophy

Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

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