Influence of repeated preexposure to arsenic on acetaminophen-induced oxidative stress in liver of male rats.
We evaluated whether repeated arsenic preexposure can increase acetaminophen-induced hepatic oxidative stress. Rats were exposed to arsenic (25 ppm; rat equivalent concentration of maximum groundwater contamination level) via drinking water for 28 days. Next day, they were given single oral administration of acetaminophen (420 or 1000 mg/kg b.w.). Hepatotoxicity was evaluated by assessing serum biomarkers, cytochrome-P450 (CYP) content, CYP3A4- and CYP2E1-dependent enzymes, lipid peroxidation and antioxidants. Arsenic or acetaminophen increased serum ALT and AST activities and depleted CYP. Arsenic decreased, but acetaminophen increased CYP-dependent enzyme activities. These agents independently increased lipid peroxidation and decreased antioxidants. Arsenic did not alter the effects of acetaminophen on serum biomarkers, caused further CYP depletion and decreased acetaminophen-mediated induction of drug-metabolizing enzymes. Arsenic enhanced the lower dose of acetaminophen-mediated lipid peroxidation and glutathione depletion with no further alterations in enzymatic antioxidants. However, arsenic attenuated the higher dose-mediated lipid peroxidation and glutathione depletion with improvement in glutathione peroxidase and glutathione reductase activities, further decrease in catalase and no alterations in superoxide dismutase and glutathione-S-transferase activities. Results show that arsenic preexposure increased the susceptibility of rats to hepatic oxidative stress induced by the lower dose of acetaminophen, but reduced the oxidative stress induced by the higher dose.
Manimaran
Ayyasamy
A
Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar 243122, Bareilly, Uttar Pradesh, India.
Sarkar
Souvendra Nath
SN
Sankar
Palanisamy
P
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000284:Administration, Oral; D000700:Analgesics / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D018053:Arsenites / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017670:Sodium Compounds / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D000700:Analgesics; D000975:Antioxidants; D018053:Arsenites; D015415:Biomarkers; D017670:Sodium Compounds; D014874:Water Pollutants, Chemical; D000082:Acetaminophen; C017947:sodium arsenite; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A