Nephrotoxicity acetaminophen

J. F. Newton, D. A. Pasino, J. B. Hook, Acetaminophen Nephrotoxicity in the Rat Quantitation of Renal Metabohc Activation in vivo, Toxicol. Appl. Pharmacol. 1985, 78, 39-46. 

C. A. Mugford, J. B. Tarloff, The Contribution of Oxidation and Deacetylation to Acetaminophen Nephrotoxicity in Female Sprague-Dawley Rats , Tox. Letters 1997, 93, 15-22. 

Acute overdose with acetaminophen (>300 mg kg ) results in hepatotoxicity and/or nephrotoxicity. Although hepatotoxicity is frequently the predominant toxicity, acetaminophen nephrotoxicity can occur in the absence of marked hepatic toxicity. In these cases, liver function returns to normal or near normal levels before the onset of nephrotoxicity. Acute acetaminophen nephrotoxicity is generally characterized as oliguric acute renal failure with acute tubular necrosis. Acetaminophen can also induce acute nephrotoxicity in therapeutic doses, but chronic alcohol intake usually accompanies renal toxicity in these patients. 

The mechanism of acute acetaminophen nephrotoxicity is related to the bioactivation of acetaminophen and/or its metabolites to highly reactive species which are capable of arylating renal macromolecules or generating reactive oxygen species. Acetaminophen hepatotoxicity is the result of conversion of acetaminophen to the reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can covalently bind to hepatic macromolecules. It is less clear what role formation of NAPQI in the kidney plays in acetaminophen nephrotoxicity. In some species (e.g., the Fischer 344 rat) deacetylation appears to be an important biotransformation step in acetaminophen nephrotoxicity, while in other species (e.g., the CD-I mouse), bioactivation does not appear to require deacetylation of acetaminophen before the ultimate nephrotoxicant species is produced. Therefore, the role of NAPQI in acute acetaminophen nephrotoxicity might be species dependent. 

Biotransformation of acetaminophen by deace-tylase enzymes in liver or kidney produces the metabolite 4-aminophenol (Figure 4). Evidence suggests that acetaminophen nephrotoxicity may result from 4-aminophenol formation. In animal studies, 4-ami-nophenol is a more potent nephrotoxicant than acetaminophen and inhibition of deacetylase enzymes also attenuates acetaminophen nephrotoxicity. Deacetylase enzymes are also present in higher levels in renal cortex, the target for acetaminophen nephrotoxicity, than in liver or renal medulla and there is a positive correlation between renal cortex... 

Stern ST, Bruno MK, Hennig GE, Horton RA, Roberts JC, Cohen SD. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-I mice I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine. Toxicol Appl Pharmacol 152005 202(2) 151-159. 

Newton, J.F., Yoshimoto, M., Bernstein, J., Rush, G.F, and Hook, J.B. (1983) Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of p-aminophenol, a metabolite of acetaminophen. Toxicol. Appl. Pharmacol. 69, 307-318. 

Acetaminophen (4.108) is hepatotoxic at higher doses, a toxicity explained by a cytochrome P450 dependent activation to A-acetyl-p-benzoquinonimine, which binds covalently to critical proteins (Chapt. 7 in [21]). However, the role of the hydrolytic step in acetaminophen-induced nephrotoxicity is not entirely clear. Early studies suggested a deacetylase-dependent activation of... 

S. G. E. Hart, W. P. Beierschmitt, J. B. Bartolone, D. S. Wyand, E. A. Kharrallah, S. D. Cohen, Evidence Against Deacetylation and for Cytochrome P450-Mediated Activation in Acetaminophen-Induced Nephrotoxicity in the CD-I Mouse , Toxicol. Appl. Pharmacol. 1991, 107, 1-15. 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

Intravenous silymarin has been demonstrated to lower mortality from Amanita mushroom poisonings, but this formulation is available only in Europe. Animal studies have demonstrated hepatic protection against alcohol, acetaminophen, and mushroom toxins and protection against hepatic fibrosis with bile duct occlusion. There is also evidence of silybin protecting against cis-platin-induced nephrotoxicity in rats. It is not yet clear whether milk thistle extract offers any renal protection to humans. 

Cytochrome P-450 and cysteine conjugate p-lyse are primarily localized in the proximal tubules, and these enzymes also contribute to the susceptibility of the proximal tubule to toxicant injury. Specifically, widely used industrial solvents such as chloroform produce tubular nephrotoxicity via cytochrome P-450 activation, and haloaUcanes and haloalkenes (e.g. trichloroethylene) are rendered toxic by cysteine conjugate (3-lyse activation [24,24a]. In addition, overdoses of acetaminophen (APAP) cause nephrotoxicity that is characterized by proximal tubular necrosis [25]. APAP undergoes cytochrome P-450-mediated activation to produce a toxic electrophile, N-acetyl-p-benzoquinon-eimine (NAPQI) [25a]. Although NAPQI is extremely reactive, it is detoxified by conjugation with reduced GSH unless NAPQI is formed in excess of the cellular capacity for GSH conjugation. The excess NAPQI is available to bind to critical cellular proteins and to induce oxidative stress, resulting in disruption of cellular homeostasis and tubular injury [26]. 

A large body of evidence is available examining the acute toxicity of acetaminophen in animal models. Mice and rats have been widely used to study the toxic effects of acetaminophen. Since the rat is relatively resistant, the mouse has been the most widely used species to study both the mechanisms of acetaminophen toxicity and to examine chemicals that potentiate or protect from the toxicity. Hepatotoxic-ity and nephrotoxicity are the two main effects associated with acute overdose of acetaminophen. Of these, death in most species is due to acute hepatic failure. LD50 values range from 350 to 4500mgkg depending on the species and the route of acetaminophen administration, mice (LD50 350-... 

Aspirin also has the potential to increase acetaminophen nephropathy. Aspirin inhibits the cyclooxygenase component of prostaglandin H synthase without effect on the prostaglandin hydroperoxidase component, while salicylic acid (the deacetylated metabolite of aspirin) decreases renal glutathione concentrations. Thus, coadministration of aspirin with acetaminophen (or phenacetin) results in a synergistic nephrotoxicity. 

Supportive measures that would complement antimicrobial effectiveness and assist recovery of the animal from the infection should be provided. In neonatal animals, care must be taken to avoid a too-rapid rate of intravenous fluid administration. Fever may serve a useful purpose in infectious diseases, and the change in body temperature may be used to assess the progress of the infection. In the presence of an infectious diseased, the only indication for an antipyretic drug, e.g. aspirin or paracetamol (acetaminophen) in dogs but not in cats metamizole (dipyrone) or sodium salicylate administered intravenously to horses, is to decrease body temperature to below a dangerous level, 41°C (105.8°F). Concurrent therapy with a NSAID and an aminoglycoside antibiotic increases the risk of nephrotoxicity. If the infection is suspected to be contagious, the diseased and in-contact animals should be isolated. 

NAG, along with other urinary enzymes, has been used to evaluate drug induced tubular damage as in the case of acetaminophen [113], 5-aminosalicyate/ sulfasalazine in patients being treated for inflammatory bowel disease [114], and the relative nephrotoxicity of differing aminoglycoside dose schedules in neonates [115]. Assess of the urinary excretion of NAG have also been reported in hypertensive patients [116] and in patients with chronic renal failure due to various causes [117]. However, to date, it is considered to be an ancillary but non-definitive marker of renal disease. 

Cooper K, Bennett WM. Nephrotoxicity of common drugs used in clinical practice. Arch Intern Med 1987 147 1213-1218. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 1994 331 1675-1679. 

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