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)

Acephate (AT) is an organophosphate (OP) insecticide. Due to their reputation for low environmental persistence, OP pesticides are often used indiscriminately resulting in detrimental exposure to humans and other nontarget species. Although the toxicity of OP compounds is primarily through blockade of neural transmission via inhibition of acetylcholinesterase, studies have revealed histopathological alterations in the renal proximal tubules, suggesting a role for additional mechanisms in renal toxicity. It is our hypothesis that Reactive Oxygen Species (ROS) may play a role in OP-induced renal tubular injury for the following reasoning. Renal tubular cells concentrate many nephrotoxic chemicals including OPs, and renal injury from many of these compounds has been shown to arise from excessive ROS production. Furthermore, it has been established that many phosphorothiolates, which are sulfur-containing OPs and constitute the class of OP compounds to which AT belongs, are S-oxidized to highly reactive intermediates within cells and tissues. Because of these considerations, we examined whether ROS play a role in OP-induced renal tubular epithelial cell (LLC-PK1) toxicity using AT as a prototype. AT produced a concentration- and time-dependent increase in cell damage in LLC-PK1 cells, measured by lactate dehydrogenase (LDH, % of total) leakage. The cytotoxicity (LDH) induced by 2500 ppm of AT over 72 h was significantly suppressed by antioxidants 2-methylaminochroman (2-MAC) and desferrioxamine (DFO). H2O2 levels were significantly elevated following exposure of LLC-PK1 cells to 2500 ppm of AT. Malondialdehyde (MDA) formation was also significantly increased in AT-exposed cells compared to the control cells, indicating the occurrence of enhanced lipid peroxidation. 2-MAC and DFO, in addition to providing cytoprotection, inhibited AT-induced MDA generation in a significant and concentration-dependent manner. Results from this study, which is the first to explore the toxic effects of AT on renal tubular cells, demonstrate that toxic action of AT on kidney cells is partly through an ROS-mediated mechanism. Based on these direct in vitro findings, we further hypothesize that oxidant stress may play a role in the pathogenesis of AT-induced acute tubular necrosis and renal dysfunction observed in cases of AT overdoses.
 ...
PMID:Role of oxidant stress and antioxidant protection in acephate-induced renal tubular cytotoxicity. 1004 44

Due to low toxicity to nontarget species and rapid degradation after its application, organophosphate (OP) remains a widely used class of pesticide. Suicidal or accidental overdose of OP can result in acute tubular necrosis. Experimental evidence shows little correlation between the renal tubular necrosis and the degree of OP-induced acetylcholinesterase inhibition, the main mechanism of OP's toxicity, suggesting the involvement of alternate mechanisms. Since reactive oxygen species (ROS) are known mediators of many toxin-induced renal injuries, this study was conducted to investigate whether ROS play a role in Bidrin (BD)-induced renal tubular epithelial cell (LLC-PK1) toxicity. BD is an OP insecticide formulation with dicrotophos as the active ingredient. LLC-PK1 cell death, determined by lactate dehydrogenase (LDH) release (% of total), rose concentration- and time-dependently after exposure of the cells to 1000, 1250, 1500, 1750, and 2000 ppm of BD for 6, 12, 24, and 48 h. Antioxidants 2-methylaminochroman (2-MAC; 0.3 to 2.5 microM) and desferrioxamine (DFO; 0.25 to 2 mM) reduced cell damage induced by 1250 ppm of BD over a 24-h incubation in a concentration-related manner. The greatest reductions in % LDH were produced by DFO 2 mM and 2-MAC 2.5 microM, both significantly lower than BD alone. H2O2 levels (micromol/mg protein per h) were significantly elevated after exposure to 1250 ppm of BD. Significantly increased malondialdehyde formation (nmol/mg protein) compared with control was also found in BD-exposed cells indicating enhanced lipid peroxidation. Malondialdehyde generation was significantly suppressed by 2-MAC and DFO. These results demonstrate that the organophosphate BD can cause direct tubular cytotoxicity, and implicate, at least in part, a role for ROS and accompanying lipid peroxidation in cytotoxicity. Based on these direct in vitro findings, it is hypothesized that, besides hypotension that often accompanies OP intoxication, OP-induced oxidative stress at the tubular level may play a role in the pathogenesis of acute tubular necrosis.
 ...
PMID:Role of reactive oxygen metabolites in organophosphate-bidrin-induced renal tubular cytotoxicity. 1044 42