Acetaminophen nephrotoxicity in male Wistar rats

Abstract

Acute acetaminophen (APAP) nephrotoxicity was studied in male Wistar rats 1 h after different APAP single doses (200, 500 and 1000 mg/kg body wt, i.p.). Significant impairments in glomerular filtration rate (GFR) and clearance of p-aminohippuric acid (ClPAH) were observed in a dose-dependent way, although tubular parameters measured, water and electrolyte fractional excretion, remained at control values, while the urine to plasma osmolality ratios (Uosm/Posm) were diminished in APAP-1000 rats (control = 2.93 +/- 0.20, APAP-1000 = 1.40 +/- 0.04). The time course of renal function was also studied in APAP-1000 mg/kg-treated animals; parallel impairments were observed in GFR, ClPAH and tubular functions. Maximal alteration was observed at 16 h and restorement began at 24 h post-injection. Glucose renal handling, either at low or at high tubular glucose loads, remained at control values. Thus, our data suggest that the early stage of acetaminophen nephrotoxicity might be due to renal hemodynamic changes which might induce an alteration in tubular function principally in distal structures of medullary tissue, as shown by the Uosm/Posm results. These effects occurred coupled with a diminution in hepatic glutathione (GSH) levels at every APAP dose and in renal GSH levels in APAP-1000 mg/kg-treated rats. Moreover, renal damage was observed both in the presence or absence of hepatic damage.

Heat shock protein 70 induction and its urinary excretion in a model of acetaminophen nephrotoxicity

“…At 48 h, liver glutathione levels were higher than control values (Table 1). Similar results were observed previously in our laboratory [9].…”

“…Sixteen hours after dosing, impairment of renal hemodynamic and tubular functions was observed. Renal function recovered 48 h after APAP administration [9]. We also reported an increment in the Triton X-100 extractability of Na + /K + ATPase in freshly isolated cortical cell suspensions incubated with APAP [10].…”

“…A group of animals received the corresponding volume of APAP vehicle (C). The dose and the time points studied were chosen based on our previous results [9].…”

Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit

“…Referral K in the group with mild dysfunction was significantly lower than that in severe renal dysfunction (p<0.0001) k Worst PT in normal group was significantly lower than mild (p<0.05), moderate (p<0.0001) ,or severe renal dysfunction (p<0.05) m Patients with moderate and severe renal dysfunction stayed longer in the intensive care unit (ITU) than those with normal renal function (p<0.0001and p<0.01, respectively) n Mortality in the group with normal renal function was significantly lower those with mild, moderate and severe renal dysfunction (p<0.0001). Those with mild renal dysfunction had lower mortality than those with moderate or severe renal dysfunction (p <0.05) renal failure, paracetamol ingestion is associated with dosedependent changes in electrolyte transport, suggesting a direct pharmacological action of paracetamol on renal tubular function [17,18]. Risk factors, such as glutathione depletion in the kidney, concomitant ingestion of nephrotoxic substances, dehydration at presentation, chronic excessive overdose of paracetamol and pre-existing liver and renal insufficiency may all increase the risk of renal injury after paracetamol overdose [19].…”

Increase in the Renal Damage Induced by Paracetamol in Rats Exposed to Ethanol Translactationally

“…Cytochrome P 450 2E1 (CYP 450 2E1), which is present in the kidney, liver and colon, is induced by ethanol, acetone and isoniazid and is the main isoform that participates in the bioactivation of APAP [8,9]. Severity of the renal damage is dependent on dosage, species differences, sex, age and degree of enzyme induction [6,10,11]. Information on the nephrotoxicity induced by APAP on the infant rat exposed to inductors of CYP 450 is scant, therefore the aim of this study was to analyze whether or not the administration of ethanol or acetone to nursing rats modifies the nephrotoxic effect of APAP in the offspring.…”