Induction of 5-oxoprolinuria in the rat following chronic feeding with N-acetyl 4-aminophenol (paracetamol)

Ghauri, Farida Y. K.; McLean, A. E. M.; Beales, Denise; Wilson, Ian D.; Nicholson, Jeremy K.

doi:10.1016/0006-2952(93)90506-r

Cited by 51 publications

(34 citation statements)

References 11 publications

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“…Therefore, women may be more susceptible to depletion of sulfated amino acids when they ingest acetaminophen. However, it should be noted that opposite findings have been reported in rodents, and the animal model of this disorder discussed above utilized male rats (50,62).…”

Section: Atp-depleting 5-oxoproline Futile Cycle May Explain Other Fementioning

confidence: 89%

“…An animal model of acquired 5-oxoprolinemia/5-oxoprolinuria can be produced in rodents by adding acetaminophen to their drinking water (50). Of importance, the addition of methionine to the drinking water together with the acetaminophen prevents development of the disorder.…”

Section: Acetaminophen and Acquired 5-oxoprolinemia/ 5-oxoprolinuriamentioning

confidence: 99%

“…Of importance, the addition of methionine to the drinking water together with the acetaminophen prevents development of the disorder. The protective mechanism of methionine is likely due to its conversion to sulfur-containing amino acids, including cysteine, which are depleted by the renal excretion of sulfated acetaminophen metabolites (50).…”

Section: Acetaminophen and Acquired 5-oxoprolinemia/ 5-oxoprolinuriamentioning

confidence: 99%

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Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Emmett

2014

Clinical Journal of the American Society of Nephrology

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SummaryThe acquired form of 5-oxoproline (pyroglutamic acid) metabolic acidosis was first described in 1989 and its relationship to chronic acetaminophen ingestion was proposed the next year. Since then, this cause of chronic anion gap metabolic acidosis has been increasingly recognized. Many cases go unrecognized because an assay for 5-oxoproline is not widely available. Most cases occur in malnourished, chronically ill women with a history of chronic acetaminophen ingestion. Acetaminophen levels are very rarely in the toxic range; rather, they are usually therapeutic or low. The disorder generally resolves with cessation of acetaminophen and administration of intravenous fluids. Methionine or N-acetyl cysteine may accelerate resolution and methionine is protective in a rodent model. The disorder has been attributed to glutathione depletion and activation of a key enzyme in the g-glutamyl cycle. However, the specific metabolic derangements that cause the 5-oxoproline accumulation remain unclear. An ATP-depleting futile 5-oxoproline cycle can explain the accumulation of 5-oxoproline after chronic acetaminophen ingestion. This cycle is activated by the depletion of both glutathione and cysteine. This explanation contributes to our understanding of acetaminophen-induced 5-oxoproline metabolic acidosis and the beneficial role of N-acetyl cysteine therapy. The ATP-depleting futile 5-oxoproline cycle may also play a role in the energy depletions that occur in other acetaminophen-related toxic syndromes.

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Section: Atp-depleting 5-oxoproline Futile Cycle May Explain Other Fementioning

confidence: 89%

Section: Acetaminophen and Acquired 5-oxoprolinemia/ 5-oxoprolinuriamentioning

confidence: 99%

Section: Acetaminophen and Acquired 5-oxoprolinemia/ 5-oxoprolinuriamentioning

confidence: 99%

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Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Emmett

2014

Clinical Journal of the American Society of Nephrology

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“…Acetaminophen is a safe, universally used analgesic, and its use by these ill patients may be merely coincidental. However, several reports suggest an association [17,18].…”

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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“…In addition, depriving the subject of essential sulfur-containing amino acids via xenobiotic detoxification also prevents their use in protein synthesis and other important sulfur-dependant anabolic processes. A consequence of this sequestration has been shown for the rat where daily oral administration of nontoxic doses of acetaminophen to juvenile animals prevented growth (16). However, understanding the cause of these effects allows rational interventions to be made and the gut microflora are an eminently ''druggable'' target (17).…”

Section: Microbiomes and Drug Metabolismmentioning

confidence: 99%

Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring

Wilson

2009

Proc. Natl. Acad. Sci. U.S.A.

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Induction of 5-oxoprolinuria in the rat following chronic feeding with N-acetyl 4-aminophenol (paracetamol)

Cited by 51 publications

References 11 publications

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Profound metabolic acidosis and oxoprolinuria in an adult

Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring

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