Regional Differences in Peroxidatic Activation of Paracetamol (Acetaminophen) Mediated by Cytochrome P450 and Prostaglandin Endoperoxide Synthetase in Rabbit Kidney

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

doi:10.1016/s0022-5347(17)53959-2

Cited by 8 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A form of cytochrome P450 was proposed to be responsible for alveolar hypoxic pulmonary vasoconstriction in dogs [36]. P450-mediated peroxidation of acetaminophen and prostaglandin endoperoxide synthetase was reported in rabbit kidney [37]. Thus began the realization that arachidonic acid [38], and many of the metabolites downstream of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid (all of them now collectively termed 'eicosanoids'), can be substrates for cytochromes P450 [39].…”

Section: (D) Roles Of Electron-donating Redox Partners In Cyp Activitiesmentioning

confidence: 99%

Human cytochromes P450 in health and disease

Nebert

Wikvall

Miller

2013

Phil. Trans. R. Soc. B

425

305

View full text Add to dashboard Cite

There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.

show abstract

Section: (D) Roles Of Electron-donating Redox Partners In Cyp Activitiesmentioning

confidence: 99%

Human cytochromes P450 in health and disease

Nebert

Wikvall

Miller

2013

Phil. Trans. R. Soc. B

425

305

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…This aspect assumes importance because microsomes are the major cellular biosynthetic sites (Rawn, 1989), but more importantly, also the site of APAP metabolism. Because of this, it is plausible that the microsomal membrane may be the primary target for the action of the reactive metabolite NAPQI (Mohandas et al, 1981;Vermeulen et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective effect of Caesalpinia gilliesii and Cajanus cajan proteins against acetoaminophen overdose-induced hepatic damage

et al. 2014

View full text Add to dashboard Cite

This study aims to evaluate two proteins derived from the seeds of the plants Cajanus cajan (Leguminosae) and Caesalpinia gilliesii (Leguminosae) for their abilities to ameliorate the toxic effects of chronic doses of acetoaminphen (APAP) through the determination of certain biochemical parameters including liver marker enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. Also, total protein content and hepatic marker enzyme, lactate dehydrogenase were studied. Moreover, liver antioxidants, glutathione (GSH), nitric oxide, and lipid peroxides were determined in this study. Hepatic adenosine triphosphatase (ATPase), adenylate energy charge (ATP, adenosine diphosphate, adenosine monophosphate, and inorganic phosphate), and phosphate potential, serum interleukin-6, tumor necrosis factor-α, and myeloperoxidase were also examined in the present study. On the other hand, histopathological examination of intoxicated and liver treated with both proteins was taken into consideration. The present results show disturbances in all biochemical parameters and hepatic toxicity signs including mild vascular congestion, moderate inflammatory changes with moderate congested sinusoids, moderate nuclear changes (pyknosis), moderate centrilobular necrosis, fatty changes, nuclear pyknosis vascular congestion, and change in fatty centrilobular necrosis liver. Improvement in all biochemical parameters studied was noticed as a result of treatment intoxicated liver with C. gilliesii and C. cajan proteins either paracetamol with or post paracetamol treatment. These results were documented by the amelioration signs in rat's hepatic architecture. Thus, both plant protein extracts can upregulate and counteract the inflammatory process, minimize damage of the liver, delay disease progression, and reduce its complications.

show abstract

Regional Differences in Peroxidatic Activation of Paracetamol (Acetaminophen) Mediated by Cytochrome P450 and Prostaglandin Endoperoxide Synthetase in Rabbit Kidney

Cited by 8 publications

References 0 publications

Human cytochromes P450 in health and disease

Human cytochromes P450 in health and disease

Renal Papillary Necrosis—40 Years On

Hepatoprotective effect of Caesalpinia gilliesii and Cajanus cajan proteins against acetoaminophen overdose-induced hepatic damage

Contact Info

Product

Resources

About