Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine

Stern, Stęphan T.; Bruno, Mary K.; Hennig, Gayle E.; Horton, Robert A.; Roberts, Jeanette C.; Cohen, Steven D.

doi:10.1016/j.taap.2004.06.030

Cited by 50 publications

(32 citation statements)

References 42 publications

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“…Another possibility is that the formation of these conjugates may contribute to glutathione depletion, which may inhibit the detoxification of reactive metabolites. These results have not been reproduced in the liver, suggesting a discrete, selective mechanism for glutathione conjugates and glutathione depletion in acetaminophen-induced renal disease [14].…”

Section: Pharmacology/pathophysiologymentioning

confidence: 86%

Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

2008

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Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity.Case: A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred

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Section: Pharmacology/pathophysiologymentioning

confidence: 86%

Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

2008

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“…Several recent papers by Stern et al suggest the kidneys as a potential source of 5-oxoproline [19,20]. In mice that receive the acetaminophen metabolite, acetaminophen-cysteine, prior to the administration of acetaminophen, renal glutathione stores are reduced and acetaminophen nephrotoxicity is enhanced [19].…”

Section: Discussionmentioning

confidence: 99%

“…In mice that receive the acetaminophen metabolite, acetaminophen-cysteine, prior to the administration of acetaminophen, renal glutathione stores are reduced and acetaminophen nephrotoxicity is enhanced [19]. Inhibition of renal tubular brush border gamma-glutamyl transpeptidase prevents the depletion of renal glutathione by this acetaminophen-cysteine adduct [20].…”

Section: Discussionmentioning

confidence: 99%

Profound metabolic acidosis and oxoprolinuria in an adult

et al. 2007

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Profound metabolic acidosis is a medical emergency that requires prompt recognition to ensure acute, appropriate management. Early, potentially life saving therapies may include hemodialysis for a toxic alcohol ingestion, insulin for diabetic ketoacidosis, antibiotics for sepsis, and in some cases drug withdrawal-such as for metformin or nucleoside analogue reverse transcriptase inhibitor associated lactic acidosis. The etiology of metabolic acidosis rarely remains elusive. We are reporting a case of profound metabolic acidosis due to accumulation of the organic acid 5-oxoproline. Case ReportA 58-year-old female presented in a confused state to the emergency department of a small community hospital. The patient's husband reported that his wife had been confused for several days. He also reported she had not been eating well, had diminished hearing, and (most recently) rapid breathing; this prompted him to bring the patient to the emergency department.Her past medical history included analgesic and diazepam abuse, alcoholism, anxiety, depression, an eating disorder, COPD, and migraines. Current medications included fluoxetine, diazepam, lansoprazole, conjugated estrogen, and sumatriptan.A physical examination revealed a disheveled, cachectic female. She was tachypneic and had difficulty hearing. Blood pressure was 171/93 mm Hg, heart rate was 80 beats per minute, respiratory rate was 35 breaths per minute, and rectal temperature was 32.5°C. Her pupils were normal and sclera were without icterus. No fruity or other odor was appreciated on her breath. Chest, heart, and abdominal exams were unremarkable. Her extremities were cool and mottled. A neurological exam at presentation did not indicate any focal-motor deficits. Profound Metabolic Acidosis and Oxoprolinuria in an Adult ABSTRACTIntroduction: Profound metabolic acidosis in critically ill adults sometimes remains unexplained despite extensive evaluation. Case Report: A 58-year-old female presented in a confused state to the emergency department; she had been confused for several days. Laboratory evaluation revealed a high anion gap metabolic acidosis and modestly elevated acetaminophen level. Lactic acid was only modestly elevated. There was no evidence of ketoacids, salicylate, methanol, or ethylene glycol. A urine sample submitted on day 1 of hospitalization revealed a markedly elevated level of 5-oxoproline.Discussion: Originally described in children with an inherited defect of glutathione synthetase, 5-Oxoproline is an unusual cause of metabolic acidosis. More recently this disturbance has been recognized in critically ill adults without a recognized inherited metabolic disorder. In most of these cases there has been the concomitant use of acetaminophen. Any causal relationship between acetaminophen and this disturbance is speculative. Conclusion:In critically ill adults with unexplained metabolic acidosis, 5-Oxoproline should be considered in the differential.

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“…It was reported that PCM is safe when administered at recommended doses (Ozkaya et al, 2010). However, its overdose is commonly associated with hepatic (Toklu et al, 2006) and renal damages (Stern et al, 2005). It is estimated that over 56,000 emergency visits and nearly 500 deaths occur in the US annually, resulting from PCM toxicity, owing to either intentional or accidental overdoses (Nourjah and Wiley, 2002).…”

Section: Introductionmentioning

confidence: 99%

Impact of Dehydroepiandrosterone in Prevention of Paracetamol Induced Nephrotoxicity in Rats

El-Karib¹

2014

American Medical Journal

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Paracetamol (PCM) overdose can cause nephrotoxicity with oxidative stress as one of the possible mechanisms mediating the event. However, Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal gland, has been shown to possess a multi-targeted antioxidant activity which is also effective against lipid peroxidation induced in various animal models and against various human disorders. In this study, the preventive effect of DHEA against PCM-induced nephrotoxicity was examined. Rats were divided into four groups containing 10 rats each, as follows: A control: Received normal saline, Vehicle treated: Received the vehicle (5% DMSO), PCM model (750 mg kg ), respectively, for 4 consecutive weeks. All treatment were given orally to animals. Our results show that co-treatment of DHEA with PCM prevented the PCM-induced nephrotoxicity and oxidative impairments of the kidney, as evidenced by a significantly reduced (p<0.05) level of serum creatinine, urea and BUN with parallel significant increases in serum protein, Cr clearance and kidneys weights. Furthermore, DHEA was able to induce a significant increment (p<0.05) of renal levels of reduced Glutathione (GSH) and activities of Superoxide Dismutase (SOD) and Glutathione Peroxidise (GPx). An effect that was accompanied with a significant decrease in renal lipid peroxides levels (MDA). The nephroprotective effects of DHEA was confirmed by a reduced intensity of renal cellular damage, as evidenced by histological findings. In conclusion, DHEA at a daily dose of 250 mg kg −1 has a protective role against PCM-induced nephrotoxicity in rats and the process is probably mediated through its antioxidant properties.

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Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine

Cited by 50 publications

References 42 publications

Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

Profound metabolic acidosis and oxoprolinuria in an adult

Impact of Dehydroepiandrosterone in Prevention of Paracetamol Induced Nephrotoxicity in Rats

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