Repeated preexposure or coexposure to arsenic differentially alters acetaminophen-induced oxidative stress in rat...

Acetaminophen (AP) is a widely used, cheap, and over-the-counter nonsteroidal anti-inflammatory drug. Its toxicity depends on the cytochrome P-450 (CYP)-mediated oxidation to the toxic metabolite N-acetyl-p-benzoquinoneimine. On the other hand, arsenic, a global groundwater and environmental contaminant of major public health concern, decreases hepatic CYP content and its dependent monoxygenase activities. We hypothesized that arsenic exposure would reduce the AP toxicity. Our aim was to evaluate the effects of repeated preexposure or coexposure to arsenic on the oxidative stress induced by a single or repeated oral administration of AP in rat kidney and its possible relationship with the effects of arsenic on certain antioxidants. Rats were exposed to arsenic through drinking water at 25 ppm for 28 days. The dosages of AP used for a single administration after arsenic preexposure for 28 days were 420 and 1000 mg kg(-1) , while for daily concurrent administration with arsenic for 28 days were 105 and 420 mg kg(-1) body weight. AP increased lipid peroxidation (LPO) in rat kidney where its acute administration caused more LPO than its subacute dosing. Repeated arsenic exposure differentially altered the AP-induced LPO. Arsenic preexposure antagonized LPO induced by the acute AP administration; in contrast, arsenic coexposure aggravated the repeated dose (AP)-mediated LPO. Arsenic-mediated alterations in renal sensitivity to LPO did not appear to be linked to the antioxidants such as reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase; nor could it be related to glutathione-S-transferase activity. The results indicated that repeated arsenic preexposure decreased susceptibility of rat kidney to acute AP-mediated oxidative stress; on the contrary, its coexposure rendered the rat kidney more vulnerable to oxidative stress induced by the repeated dosing of AP.