Metabolic oxidation of acetaminophen (Paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney

Mohandas, Janardanan; Duggin, Geoffrey G.; Horvath, John S.; Tiller, David J.

doi:10.1016/0041-008x(81)90415-4

Cited by 84 publications

(20 citation statements)

References 22 publications

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“…Reduction of the protoporphyrin radical cation would prevent the formation of the tyrosyl radical. There is abundant evidence that ApAP and other reductants act to reduce this higher oxidative state of the PGHS-peroxidase and other peroxidases to the ferric or ''resting'' state, a process in which ApAP serves as a cosubstrate for the peroxidases (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). By contrast, ibuprofen, indomethacin, and flurbiprofen, inhibitors that block access of substrate to the PGHS-cyclooxygenase catalytic site, do not act as cosubstrates of the PGHS-peroxidase (28).…”

Section: Discussionmentioning

confidence: 99%

“…After finding that the action of ApAP in HUVECs is to inhibit the PGHSs, the determinants of the selectivity of this inhibition for endothelial cells were investigated. The basis for these investigations was derived from the accumulating evidence that ApAP inhibits the PGHSs by reducing the higher oxidation state of the enzymes (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). The PGHS-peroxidase, by reduction of a hydroperoxide to its alcohol, oxidizes the enzyme from its resting state (ferric heme) to the ferryloxo-protoporphyrin radical cation, which by intramolecular electron transfer generates the tyrosyl radical in the PGHS-cyclooxygenase site that is required for oxygenation of arachidonic acid (AA) (35)(36)(37)(38).…”

mentioning

confidence: 99%

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Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H ₂ synthases

Boutaud

Aronoff

Richardson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

207

204

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H ₂ synthases

Boutaud

Aronoff

Richardson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

207

204

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“…Acetaminophen undergoes oxidative metabolism by prostaglandin H synthase to a reactive quinoneimine that is conjugated to GSH (156,157). It has been argued that the coadministration of aspirin will serve to deplete GSH (possibly by interfering with the pentose shunt) as a result of which the reactive metabolite of acetaminophen then produces lipid peroxides and arylation of tissue proteins, ultimately resulting in RPN (52).…”

Section: The Bioactivhtioit Of Papillotoxins In Renal Medullary Intermentioning

confidence: 99%

Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

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Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized as a major class of therapeutic agent that causes renal papillary necrosis (RPN). Over the last decade a broad spectrum of other therapeutic agents and many chemicals have also been rcportcd that have the potential to cause this lesion in animals and man. There is consensus that RPN is the primary lesion that can progress to cortical degeneration; and it is only at this stage that the lesion is easily diagnoscd. In the absence of sensitive and selective noninvasive biomarkers of RPN there is still no clear indication of which compound, under what circumstances, has the greatest potential to cause this lesion in man. Attempts to mimic RPN in rodents using analgesics and NSAIDs have not provided robust models of the lesion. Thus, much of the research has concentrated on those compounds that cause an acute or subacute RPN as the basis by which to study the pathogenesis of the lesion. Based on the mechanistic understanding gleaned from these model compounds it has been possible to transpose an understanding of the underlying processes to the analgesics and NSAIDs. The mechanism of RPN is still controversial. There are data that support microvascular changes and local ischemic injury as the underlying cause. Alternatively, several model papillotoxins, some analgesics, and NSAIDs target selectively for the medullary interstitial cells, which is the earliest reported aberration, after which there are a series of degenerative processes affecting other renal cell types. Many papillotoxins have the potential to undergo prostaglandin hydroperoxidase-mediated metabolic activation, specifically in the renal medullary interstitial cells. These reactive intermediates, in the presence of large quantities of polyunsaturated lipid droplets, result in localized and selective injury of the medullary interstitial cells. These highly differentiated cells do not repair, and it is generally accepted that continuing insult to these cells will result in their progressive erosion. The loss of these cells is thought to be central to the degenerative cascade that affects the cortex. There is still a need to understand better the primary mechanism and the secondary consequences of RPN so that the risk of chemical agents in use and novel molecules can be fully assessed.

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“…Under normal conditions, acetaminophen is mainly metabolized by undergoing sulfation and glucuronidation (2). It has been proposed that a small amount of drug goes through the cytochrome P450 mixed function oxidase system and is metabolized into the reactive intermediate N-acetyl-P-benzoquinoneimine (NAPQI), 1 which is in turn detoxified by reaction with glutathione (3,4). When large quantities of acetaminophen are consumed, the three detoxification pathways become saturated.…”

mentioning

confidence: 99%

Acetaminophen Toxicity

Mirochnitchenko¹,

Weisbrot-Lefkowitz²,

Reuhl

et al. 1999

Journal of Biological Chemistry

109

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Acetaminophen is one of the most extensively used analgesics/antipyretics worldwide, and overdose or idiopathic reaction causes major morbidity and mortality in its victims. Research into the mechanisms of toxicity and possible therapeutic intervention is therefore essential. In this study, the response of transgenic mice overexpressing human antioxidant enzymes to acute acetaminophen overdose was investigated. Animals overexpressing superoxide dismutase or plasma glutathione peroxidase demonstrated dramatic resistance to acetaminophen toxicity. Intravenous injection of glutathione peroxidase provided normal mice with nearly complete protection against a lethal dose of acetaminophen. Surprisingly, animals overexpressing intracellular glutathione peroxidase in the liver were significantly more sensitive to acetaminophen toxicity compared with nontransgenic littermates. This sensitivity appears to be due to the inability of these animals to efficiently recover glutathione depleted as a result of acetaminophen metabolism. Finally, the results suggest that glutathione peroxidase overexpression modulates the synthesis of several acetaminophen metabolites. Our results demonstrate the ability of glutathione peroxidase levels to influence the outcome of acetaminophen toxicity.

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Metabolic oxidation of acetaminophen (Paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney

Cited by 84 publications

References 22 publications

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H ₂ synthases

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H ₂ synthases

Renal Papillary Necrosis—40 Years On

Acetaminophen Toxicity

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Metabolic oxidation of acetaminophen (Paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney

Cited by 84 publications

References 22 publications

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H 2 synthases

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H 2 synthases

Renal Papillary Necrosis—40 Years On

Acetaminophen Toxicity

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Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H ₂ synthases

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H ₂ synthases