Repeated acetaminophen dosing in rats: adaptation of hepatic antioxidant system
| Autor: | F Elcock, J M Birmingham, Peter J. O'Brien, P J Bugelski, A Swain, Mark R Slaughter, R W Greenhill |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Antioxidant Health Toxicology and Mutagenesis medicine.medical_treatment Glutathione reductase Toxicology medicine.disease_cause Thiobarbituric Acid Reactive Substances Antioxidants Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Malondialdehyde medicine TBARS Animals Acetaminophen chemistry.chemical_classification Glutathione Peroxidase biology Superoxide Dismutase Glutathione peroxidase Body Weight Alanine Transaminase General Medicine Glutathione Organ Size Catalase Adaptation Physiological Rats Up-Regulation 030104 developmental biology Endocrinology Glutathione Reductase chemistry Alanine transaminase Liver biology.protein Glucose-6-Phosphatase 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Humanexperimental toxicology. 19(5) |
| ISSN: | 0960-3271 |
| Popis: | Repeated dosing of acetaminophen (paracetamol) to rats is reported to decrease their sensitivity to its hepatotoxic effects, which are associated with oxidative stress and glutathione depletion. We determined if repeated acetaminophen dosing produced adaptive response of key antioxidant system enzymes. Male rats (Sprague-Dawley, 10 weeks) were given 800, 1200, or 1600 mg/kg/day acetaminophen by oral gavage for 4 days. Liver was assayed for oxidative stress and antioxidant markers: malondialdehyde (MDA), thiobar-bituric acid reactive substance (TBARS), total antioxidant status (TAS), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD), catalase (CAT), and superoxide dismutase (SOD), and alanine transaminase (ALT) as a marker of hepatocellular injury. Acetaminophen at 1200/1600 mg/kg decreased GSH 26/47%, GPx 21/26%, CAT 35/28%, SOD 21/12%; and TAS 28/18% (correlated with CAT, r=0.91; SOD, r=0.66; GPx, r = 0.45). Despite antioxidant deficiencies, and no TBARS change, MDA decreased 26%/33%/37% at 800/1200/1600 mg/kg, which correlated with increased GR (61%/62%/76%, r = 0.77) and G6PD (130%/110%/190%, r = 0.78). Both MDA (r = 0.68) and G6PD (r = 0.71) correlated with hepatic ALT, which decreased 27%o/43%/48%, respectively. Resistance to acetaminophen hepatotoxicity produced by repeated exposure is partially attributable to upregulation of hepatic G6PD and GR activity as an adaptive and protective response to oxidative stress and glutathione depletion. |
| Databáze: | OpenAIRE |
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