Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat

Fowler, Lynn M.; Foster, John R.; Lock, Edward A.

doi:10.1007/bf01974068

Cited by 33 publications

(11 citation statements)

References 36 publications

(35 reference statements)

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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.…”

Section: Discussionmentioning

confidence: 93%

“…Other studies revealed that PAP can form a 4-aminophenoxy free radical that oxidizes to yield benzoquinoneimine, which can bind covalently to renal proteins (Fowler et al, 1993). 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.…”

Section: Discussionmentioning

confidence: 98%

“…Several toxic GSH conjugates, including 4-amino-3-S-glutathionylphenol (PAP-SG), were found in kidney cell preparations in vitro and in bile of PAP-treated rats (Fowler et al, 1991;Klos et al, 1992). PAP-SG was more toxic than PAP itself, suggesting further that GSH conjugate(s) might be responsible for toxicity of PAP (Fowler et al, 1993).…”

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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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

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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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“…For example, NADPH reduced tetrachloro-l,4-benzoquinone to tetrachloro-l,4-benzene-diol in aqueous solution in the absence of enzymatic activity (Chang et al, 1996). In addition, Lock and colleagues showed that PAP-induced toxicity in vivo and in vitro could be prevented by ascorbic acid, another reducing agent (Fowler et al, 1993;Lock et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Coincubation of Rat Renal Proximal Tubules with Hepatic Subcellular Fractions Potentiates the Effects of para-Aminophenol

1997

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Treatment of rats with para-aminophenol (PAP) (300 mg/kg ip) produced decreases in renal nonprotein sulfhydryl (NPSH) content, oxygen consumption, and adenine nucleotide concentrations 2-4 hr following administration. In contrast, incubation of rat renal tubules with up to 1 mM PAP for 4 hr produced inconsistent changes in renal tubules. This discrepancy suggested that extrarenal metabolism of PAP may be involved in PAP bioactivation and nephrotoxicity. We designed the present studies to test the hypothesis that hepatic metabolism of PAP potentiates the effects of PAP on renal tubules. Incubation of renal tubules with 0.5 mM PAP and 10 mg protein from hepatic postmitochondrial supernatant (S9 fraction) in the absence of glutathione (GSH) for 4 hr did not alter renal oxygen consumption or adenine nucleotide metabolite concentrations. We observed no changes when we incubated tubules with 0.5 mM PAP and 1 mM GSH in the absence of hepatic S9 fraction. However, incubation of renal tubules with 0.5 mM PAP, 1 mM GSH, and 10 mg hepatic S9 protein for 4 hr significantly decreased renal oxygen consumption and adenosine triphosphate and total nucleotide concentrations. These data suggest that the effects of PAP in renal tubules may be potentiated by enzymatic metabolism of PAP, possibly involving oxidation and GSH conjugation. From experiments using hepatic microsomes or cytosol instead of S9 fraction, we found that changes were produced when we incubated tubules with PAP in the presence of hepatic microsomes, but not cytosol. These data suggest that hepatic microsomal metabolism of PAP may contribute to the production of changes in renal tubules in vitro. PAP-induced changes in renal proximal tubules were prevented when we included a 0-nicotinamide adenine dinucleotide phosphate (NADPH) generating system in the incubation medium. The protective effect of NADPH persisted when microsomes were inactivated by incubation with 1-aminobenzotriazole, a cytochrome P450 inhibitor. These data suggest that cytochrome P450-dependent oxidation is not involved in the production or prevention of PAP-induced changes in renal tubules. The enzyme(s) responsible for PAP bioactivation and the mechanism(s) by which NADPH protects renal 1 To whom correspondence should be addressed. These studies were supported by USPHS Grant GM51361.tubules from PAP-induced decrements in oxygen consumption and adenine nucleotide concentrations are currently unclear, c 1997 Soday of Toxicology.

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“…These toxicants are formed endogenously (211). 4-Aminophenol caused selective necrosis to the pars recta of the proximal tubules of the kidney (212), but ascorbic acid decreased the degree of oxidation of the aminophenol and the toxic effect (213). It was postulated that a 4-aminophenoxy free radical formed that was converted to a benzoquinoneimine that binds to cellular macromolecules.…”

Section: Toxic Effectsmentioning

confidence: 99%

Aromatic Nitro and Amino Compounds

Bingham¹,

McGowan²

2012

Patty's Toxicology

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Logically, aromatic nitro and amino compounds should be discussed together because their toxic responses are often similar due to a common metabolic intermediate. Synthetically, amines are generally derived from nitro compounds, but in some cases nitro compounds can be prepared through amines when other methods fail to afford specific compounds. There are good and bad attributes to these types of compounds. Some act as sensitizers and contingent on physical properties may be absorbed through the skin or mucous membranes. They may also cause methemoglobinemia, depending on such factors as the structure and the particular organism. Some members of this class are known as animal and human carcinogens; for humans, the urinary bladder is the most prominent target organ. Nevertheless, these compounds and their derivatives have enlivened our world through their use as dyestuff intermediates or as photographic chemicals, they alleviate pain as components of widely used analgesics, and they cushion or insulate us through their use in flexible and rigid foams. Other important uses include production of pesticides, including herbicides and fungicides, as ingredients in adhesives, paints and coatings, antioxidants, explosives, optical brighteners, rubber ingredients, and as intermediates in many other products.

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Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat

Cited by 33 publications

References 36 publications

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

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

Coincubation of Rat Renal Proximal Tubules with Hepatic Subcellular Fractions Potentiates the Effects of para-Aminophenol

Aromatic Nitro and Amino Compounds

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