ReviewClinical journal of the American Society of Nephrology : CJASN2014
Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle.
Review in Clinical journal of the American Society of Nephrology : CJASN, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 56 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 101 citations in OpenAlex.
- Intra-articular treatment of knee osteoarthritis: from anti-inflammatories to products of regenerative medicine.The Physician and sportsmedicine · 2016Pooled it
- Discriminating high-risk cervical Human Papilloma Virus infections with urinary biomarkers via non-targeted GC-MS-based metabolomics.PloS one · 2018Trial
- Metabolomics Effects of Folding Correction in Retinitis Pigmentosa Rhodopsin Mutant P23A.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Targeted metabolomics of organic and amino acids in giraffe milk during mid- to late-lactation.Metabolomics : Official journal of the Metabolomic Society · 2026Article
- A Targeted Metabolomic Assessment of Oral Glutathione Bioavailability and Safety in Humans: A Randomized Crossover Clinical Trial.Antioxidants (Basel, Switzerland) · 2026Article
- An Unusual Case of 5-Oxoproline Acidosis.Kidney medicine · 2026Article
- 2-line Ferrihydrite Enhance Microbial Synthesis of Plant Biostimulants in Composted Biosolid by Regulating Phyla Pseudomonadota and Actinomycetota.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Preksha Dhyana meditation modulates the serum metabolome in healthy and meditation-naïve participants.Frontiers in molecular biosciences · 2026Article
- Causal mediation of plasma metabolomics in pancreatitis: A Mendelian randomization study.Medicine · 2025Article
- Multiorgan Failure Secondary to Intentional Acetaminophen Overdose-Induced Methemoglobinemia.Cureus · 2025Article
- Acetaminophen induced high anion gap metabolic acidosis: a potentially under-recognized consequence from a common medication.Pediatric nephrology (Berlin, Germany) · 2025Article
- Multi-omics analysis reveals glutathione metabolism-related immune suppression and constructs a prognostic model in lung adenocarcinoma.Frontiers in immunology · 2025Article
- Drug-Related Pyroglutamic Acidosis: Systematic Literature Review.Journal of clinical medicine · 2024Article
- A case report of Paracetamol related pyroglutamic acidosis: mind the gap in a malnourished patient.BMC nephrology · 2024Article
- Pyroglutamic acidosis in the setting ofClinical case reports · 2024Article
- Mind the Anion Gap: 5-Oxoproline-Induced High Anion Gap Metabolic Acidosis in End-Stage Renal Disease.Cureus · 2024Article
- Review
- Gas Chromatography-Mass Spectrometry Reveals Stage-Specific Metabolic Signatures of Ankylosing Spondylitis.Metabolites · 2023Article
- Pyroglutamic acidosis caused by the combination of two common medicines prescribed in everyday practice.Oxford medical case reports · 2023Article
- Pyroglutamic Acidosis - An Underrecognised Entity Associated with Acetaminophen Use.Romanian journal of anaesthesia and intensive care · 2023Article
Corrections and comments
- Erratum issuedCorrection.2017
Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The 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 γ-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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.