Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:The role of gamma-glutamyl transpeptidase in the nephrotoxicity of an Agaricus bisporus metabolite. 610 87

To elucidate the renal injury induced by gold treatment, we administered various doses of gold sodium thiomalate (GST) to Wistar rats and investigated alterations in the urinary enzyme activity, gamma-glutamyl transpeptidase (gamma GTP) and N-acetyl-beta-glucosaminidase (NAG) activity, and histochemical change of enzymes, gamma GTP, alkaline phosphatase (ALP) and acid phosphatase (ACP) activity in the renal tissue. The single administration of a large dose of gold salts induced acute tubular necrosis and enzyme leakage was detected histochemically without damage to the glomerulus. After chronic administration of small doses of gold salts, the urinary gamma GTP activities gradually increased, but urinary NAG activities did not. These findings suggested that the change in urinary enzyme activities, which leaked from inside of brushborder or lysosome, indicated the degree or localization of tubular damage, because renal tubules were selectively injured by gold salts.
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PMID:Changes in urinary enzyme activity and histochemical findings in experimental tubular injury induced by gold sodium thiomalate. 886 77

Mercury chloride (HgCl2) has a potent nephrotoxic effect. Most of Hg2+ existing in plasma following HgCl2 exposure forms a complex with sulfhydryl-containing ligands such as albumin and glutathione (GSH). The Hg(2+)-GSH complex is filtered in the glomeruli of the kidney and degraded into Hg(2+)-cysteine in the proximal tubules by the combined action of gamma-glutamyl transpeptidase and dipeptidase present in the epithelial cells. The degradation product is then incorporated and accumulated into the proximal tubule epithelial cells. The accumulated Hg2+ in the epithelial cells finally causes acute tubular necrosis (ATN) by its cytotoxic effect. At present, it is believed that tubular obstruction resulting from ATN triggers the onset of HgCl2-induced acute renal failure (ARF). A progressive fall in glomerular filtration rate (GFR) contributes to the progression of HgCl2-induced ARF. The fall in GFR may be caused by an increment in afferent arteriole resistance (RA) and a decrement in the ultrafiltration coefficient (Kf) due to mesangial cell contraction. These changes in RA and Kf may be attributed to the increased action of the vasoconstrictors, angiotensin II and endothelin-1 and to the decreased action of the vasodilator, nitric oxide observed at the glomerulus level of HgCl2-induced ARF. Accordingly, the imbalance between these vasoactive substances appears to play an important role in the progression of HgCl2-induced ARF due to reducing GFR. Further studies, however, remain to elucidate the mechanisms involved.
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PMID:[HgCl2-induced acute renal failure and its pathophysiology]. 952 59