Pyruvate reduces 4-aminophenol in vitro toxicity

Harmon, R. Christopher; Kiningham, Kinsley K.; Valentovic, Monica

doi:10.1016/j.taap.2005.10.008

Cited by 22 publications

(16 citation statements)

References 31 publications

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“…The inability to protect LLC-PK 1 cells from toxicity by including pyruvate is at odds with previous reports in which pyruvate provided partial protection from PAP toxicity in rat renal cortical slices (Harmon et al, 2006). It is possible that differences in route of entry might contribute to the disparity.…”

Section: Intracellular Events In Pap Toxicitymentioning

confidence: 71%

“…These reactive intermediates may be responsible for mitochondrial damage and covalent binding observed with PAP (Crowe et al, 1977(Crowe et al, , 1979Kruidering et al, 1994). However, PAP has also been shown to cause lipid peroxidation, measured as 4-hydroxynonenal-adducted proteins (Harmon et al, 2005(Harmon et al, , 2006. The ability of PAP to generate reactive oxygen intermediates has not been investigated previously.…”

Section: Discussionmentioning

confidence: 99%

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Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Foreman¹,

Tarloff²

2008

Toxicology and Applied Pharmacology

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Para-aminophenol (PAP) causes nephrotoxicity by biochemical mechanisms that have not been fully elucidated. PAP can undergo enzymatic or non-enzymatic oxidation to form reactive intermediates. Using modulators of reactive oxygen species (ROS), the role of ROS in PAP toxicity in LLC-PK 1 cells was investigated. ROS formation was determined using a fluorescein derivative and viability using alamarBlue. Following treatment of cells with PAP, ROS formation occurred prior to loss of cell viability. Several modulators of ROS were used to identify the pathways involved in PAP toxicity. Viability was improved with catalase treatment, while viability was decreased when cells were treated with superoxide dismutase (SOD). Both catalase and SOD exert their effects outside of cells in the incubation medium, since there was no evidence of uptake of these enzymes in LLC-PK 1 cells. In cell-free incubations, hydrogen peroxide (H 2 O 2 ) was produced when 0.5 mM PAP was included in the incubation medium. Further, SOD greatly increased and catalase greatly decreased H 2 O 2 production in these cell-free incubations. These data suggest that H 2 O 2 formed in the incubation medium contributes to loss of viability following PAP treatment. When cells were coincubated with 0.5 mM PAP and tiron, pyruvate, bathocuproine, 1, 10-phenanthroline, or dimethylthiourea (DMTU), ROS formation was decreased. However, there was minimal improvement in cell viability. Paradoxically, DMTU exacerbated PAP-induced loss of viability. These data suggest ROS are generated in cells exposed to PAP but these species are not the predominant cause of cellular injury.

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Section: Intracellular Events In Pap Toxicitymentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Foreman¹,

Tarloff²

2008

Toxicology and Applied Pharmacology

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“…Ascorbate afforded protection from PAP nephrotoxicity in vivo and in vitro (Fowler et al, 1993;Song et al, 1999;Hallman et al, 2000;Harmon et al, 2005Harmon et al, , 2006, suggesting a role for a free radical metabolite. The possibility of redox cycling of a PAP metabolite was mentioned by Rankin et al (1996), and evidence of lipid peroxidation in rat kidneys and kidney slices has been presented (Kanbak et al, 1996;Harmon et al, 2005Harmon et al, , 2006. In LLCPK1 kidney cells exposed to PAP, generation of reactive oxygen species (ROS) and cytotoxicity occurred; however, ROS scavengers failed to provide protection, suggesting that ROS are not the main cause of PAP-induced cytotoxicity in these cells (Foreman and Tarloff, 2008).…”

Section: Discussionmentioning

confidence: 95%

“…However, the acute renal toxicity of APAP has been attributed to formation of PAP (Newton et al, 1985a,b). PAP exposure in vivo or in vitro led to glutathione (GSH) depletion in kidney cells (Shao and Tarloff, 1996;Song et al, 1999;Harmon et al, 2005Harmon et al, , 2006). An inhibitor of GSH biosynthesis protected rats from PAPinduced renal injury (Gartland et al, 1990;Song et al, 1999), and GSH depletion decreased PAP cytotoxicity in renal cells in vitro (Klos et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…First, the metabolism of APAP by P450s is limited by inactivation of P450s by reactive NAPQI (Snawder et al, 1994), thereby potentially slowing elimination of APAP and consequently maintaining intracellular concentrations available for deacetylation to PAP. Second, in HPCs compromised by the early-acting P450-dependent mechanism, ATP production is impaired (Andersson et al, 1990;Burcham and Harman, 1991;Harmon et al, 2006). The resultant decrease in ATP availability would be expected to slow NAT-dependent reacetylation of PAP, because formation of acetylCoA as a donor molecule for this reaction requires ATP.…”

Section: Discussionmentioning

confidence: 99%

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A Cytochrome P450–Independent Mechanism of Acetaminophen-Induced Injury in Cultured Mouse Hepatocytes

Miyakawa

Albee

Letzig

et al. 2015

J Pharmacol Exp Ther

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Mouse hepatic parenchymal cells (HPCs) have become the most frequently used in vitro model to study mechanisms of acetaminophen (APAP)-induced hepatotoxicity. It is universally accepted that APAP hepatocellular injury requires bioactivation by cytochromes P450 (P450s), but this remains unproven in primary mouse HPCs in vitro, especially over the wide range of concentrations that have been employed in published reports. The aim of this work was to test the hypothesis that APAPinduced hepatocellular death in vitro depends solely on P450s. We evaluated APAP cytotoxicity and APAP-protein adducts (a biomarker of metabolic bioactivation by P450) using primary mouse HPCs in the presence and absence of a broad-spectrum inhibitor of P450s, 1-aminobenzotriazole (1-ABT). 1-ABT abolished formation of APAP-protein adducts at all concentrations of APAP (0-14 mM), but eliminated cytotoxicity only at small concentrations (≦5 mM), indicating the presence of a P450-independent mechanism at larger APAP concentrations. P450-independent cell death was delayed in onset relative to toxicity observed at smaller concentrations. p-Aminophenol was detected in primary mouse HPCs exposed to large concentrations of APAP, and a deacetylase inhibitor [bis (4-nitrophenyl) phosphate (BNPP)] significantly reduced cytotoxicity. In conclusion, APAP hepatocellular injury in vitro occurs by at least two mechanisms, a P450-dependent mechanism that operates at concentrations of APAP ≦ 5 mM and a P450-independent mechanism that predominates at larger concentrations and is slower in onset. p-Aminophenol most likely contributes to the latter mechanism. These findings should be considered in interpreting results from APAP cytotoxicity studies in vitro and in selecting APAP concentrations for use in such studies.

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Fast determination of paracetamol and its hydrolytic degradation product p‐aminophenol by capillary and microchip electrophoresis with contactless conductivity detection

et al. 2022

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is one of the most extensively used analgesics and antipyretic drugs to treat mild and moderate pain. P-aminophenol (PAP), the main hydrolytic degradation product of PAC, can be found in environmental water. Recently, CE has been developed for the detection of a wide variety of chemical substances. The purpose of this study is to develop a simple and fast method for the detection and separation of PAC and its main hydrolysis product PAP using CE and microchip electrophoresis with capacitively coupled contactless conductivity detection. The determination of these compounds using microchip electrophoresis with capacitively coupled contactless conductivity detection is being reported for the first time. The separation was run for all analytes using a BGE (20 mM β-alanine, pH 11) containing 14% (v/v) methanol. The RSDs obtained for migration time were less than 4%, and RSDs obtained for peak area were less than 7%. The detection limits (S/N = 3) that were achieved ranged from 0.3 to 0.6 mg/L without sample preconcentration. The presented method showed rapid analysis time (less than 1 min), high efficiency and precision, low cost, and a significant decrease in the consumption of reagents. The microchip system has proved to be an excellent analytical technique for fast and reliable environmental applications.

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Pyruvate reduces 4-aminophenol in vitro toxicity

Cited by 22 publications

References 31 publications

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

Contribution of reactive oxygen species to para-aminophenol toxicity in LLC-PK1 cells

A Cytochrome P450–Independent Mechanism of Acetaminophen-Induced Injury in Cultured Mouse Hepatocytes

Fast determination of paracetamol and its hydrolytic degradation product p‐aminophenol by capillary and microchip electrophoresis with contactless conductivity detection

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