| The role of gamma-glutamyl transpeptidase in the nephrotoxicity of an Agaricus bisporus metabolite. | |
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MedLine Citation:
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PMID: 6106387 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mushroom metabolite gamma-L-glutaminyl-3,4-dihydroxybenzene (GDHB) was found to have an LD50 of 100 to 200 mg/kg in neonatal C57Bl/6J mice. Adult mice given 200 mg/kg GDHB showed histopathologic evidence of proximal convoluted tubular injury as early as 2 hours after injection, which progressed by 24 hours to profound acute tubular necrosis. Focal acinar epithelial cell necrosis in the pancreas was also observed. The time course and location of the injury suggested that appearance of the ultimate toxic metabolite could be due to cleavage of GDHB by gamma-glutamyl transpeptidase (GGTP). The reaction in vitro of GDHB with crude porcine GGTP resulted in the release of 4-amino-catechol which air oxidized to 2-hydroxy--4-iminoquinone (HIQ), a known sulfhydryl reagent and cytotoxic compound. Synthesis of N2-methyl-gamma-glutaminyl-3,4-dihydroxybenzene (MeGDHB) provided a compound whose oxidized derivatives, when compared with those of GDHB, had similar half-wave potentials and visible absorption maxima. MeGDHB was resistant to cleavage by GGTP and was without apparent toxicitiy at 2-3 times the LD50 of GDHB. Therefore, cleavage by GGTP, an enzymatic transformation accessible to GDHB but unavailable to MeGDHB, is proposed as the mechanism of activation of the mushroom metabolite. The following pathogenic sequence is indicated: 1) release of 4-aminocatechol from GDHB by the action of GGTP and 2) irreversible injury resulting both from the generation of free radicals by the autoxidation of 4-aminocatechol and from the reaction of HIQ with cellular nucleophils, particularly sulfhydryl groups. |
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Authors:
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K Boekelheide; D G Graham; P D Mize; F S Vogel |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The American journal of pathology Volume: 100 ISSN: 0002-9440 ISO Abbreviation: Am. J. Pathol. Publication Date: 1980 Sep |
Date Detail:
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Created Date: 1980-11-25 Completed Date: 1980-11-25 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 651-62 Citation Subset: AIM; IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Agaricales
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metabolism* Animals Animals, Newborn Catecholamines / toxicity Chemistry, Physical Glutamine / analogs & derivatives*, toxicity Kidney / drug effects* Kidney Tubular Necrosis, Acute / chemically induced Mice Mice, Inbred C57BL Pancreas / drug effects Physicochemical Phenomena gamma-Glutamyltransferase / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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CA-19013/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Catecholamines; 13047-04-6/4-aminocatechol; 56-85-9/Glutamine; 58298-77-4/agaridoxin; 76500-09-9/N(2)-methyl-gamma-L-glutaminyl-3,4-dihydroxybenzene; EC 2.3.2.2/gamma-Glutamyltransferase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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