http://informahealthcare.com/dct ISSN: 0148-0545 (print), 1525-6014 (electronic) Drug Chem Toxicol, Early Online: 1–5 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/01480545.2014.928722
REVIEW ARTICLE
Mechanisms of interaction of the N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity
Drug and Chemical Toxicology Downloaded from informahealthcare.com by Dalhousie University on 06/28/14 For personal use only.
Milena S´ciskalska, Mariola S´liwin´ska-Mosson´, Magdalena Podawacz, Waldemar Sajewicz, and Halina Milnerowicz Department of Biomedical and Environmental Analysis, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
Abstract
Keywords
Context: Epidemiological studies have demonstrated that chronic use of N-acetylp-aminophenol is correlated with the occurrence of renal dysfunction. Objective: Aim of this study was to review the literature on the mechanisms of interaction N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity. Methods: We present a literature review of studies published in English language on the damage effects of N-acetyl-p-aminophenol on the kidneys, accessed through PubMed database. Results: The pathogenesis of drug-induced nephrotoxicity attributed to the action of cytochrome P450 enzymes, prostaglandin endoperoxide synthase (PGES) and N-deacetylase. The metabolism of N-acetyl-p-aminophenol with the participation of PGES more explicit is in the core of kidney, whereas cytochrome P450 enzymes play role in the renal cortex. Due to the action of cytochrome P450 and N-deacetylase, a very reactive N-acetyl-p-benzochinoimine (NAPQI) is formed. The result of the catalytic activity of PGES is p-benzoquinone (PBQI) production. The formation of NAPQI and PBQI is accompanied by the production of free radicals. Metabolites can connect covalently with sulfhydryl groups of renal proteins, what can cause the injury of proximal tubules. N-acetyl-p-aminophenol may initiate the apoptosis process involving activation of caspase-9 and caspase-3, but also caspase-12 as a result of generation of free radicals. Conclusions: The process of NAPQI and PBQI formation can increase oxidative stress that promotes the kidneys damage. The ability of metabolites to produce covalent bonds with sulfhydryl groups of proteins can increase the nephrotoxicity. It was assumed that the induction of apoptosis in renal tubular epithelial cells, and not necrosis underlies the nephrotoxic potential of N-acetyl-p-aminophenol.
Cytochrome P450, N-acetyl-p-aminophenol, N-acetyl-p-benzochinoimine
Introduction N-acetyl-p-aminophenol is the drug derived from the group of non-narcotic analgesic and antipyretic drug for the treatment of mild-to-moderate pain (Chandrasekharan et al., 2002). It is a common ingredient in many over-the-counter analgesics, which promotes rapid overdose and numerous cases of poisoning. The risk of poisoning in human can be enhanced, while hepatic enzymes activities involved in N-acetylp-aminophenol metabolism are reduced, e.g. UDP-glucuronosyl transferases deficient in Gilbert’s syndrome (McGill & Jaeschke, 2013). The risk of N-acetyl-p-aminophenol poisoning is increased during chronic alcohol consumption, which can induce a metabolic activation of N-acetyl-p-aminophenol to harmful metabolites. However, acute alcohol exposure can reduce a liver injury, what is controversial (Manchanda et al., 2013; McGill & Jaeschke, 2013). Likewise, isoniasyd can
Address for correspondence: Milena S´ciskalska, Department of Biomedical and Environmental Analysis, Wroclaw Medical University, 211 Borowska St., 50-556 Wrocław, Poland. Tel: (0 71) 784 01 78. Tel/Fax: (0 71) 784 01 72. E-mail: [email protected]
History Received 12 February 2014 Revised 20 May 2014 Accepted 23 May 2014 Published online 24 June 2014
enhance or inhibit N-acetyl-p-aminophenol metabolism in dose-dependent manner (McGill & Jaeschke, 2013). These substances can be a risk factors for N-acetyl-p-aminophenol poisoning, because can intensify the effect of therapeutic dose, which may became a toxic dose. N-acetyl-p-aminophenol overdose remains one of the most important common poisonings in many parts of the world (Duffull & Isbister, 2013). In the United States, N-acetyl-paminophenol overdose is responsible for 50-80 000 emergency department visits each year, 26 000 hospitalizations and 500 deaths (McGill & Jaeschke, 2013). A toxic dose of N-acetyl-p-aminophenol is not known. Toxic dose is defined empirically as a dose that is known to cause toxicity. Various guidelines suggest different toxic doses. Most international guidelines recommend 200 mg/kg of body weight or 10 g as a toxic dose (Duffull & Isbister, 2013). Especially often dangerous complication of the N-acetyl-p-aminophenol overdose is liver damage (Cermik et al., 2013). However, chronic use of N-acetyl-p-aminophenol correlating with renal dysfunction in epidemiological studies were shown (Herrero et al., 2001; Le Vaillant et al., 2013). The aim of this study was to review the literature on the mechanisms of interaction
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N-acetyl-p-aminophenol nephrotoxicity.
Drug Chem Toxicol, Early Online: 1–5
metabolites
in
terms
of
Materials and methods We present a literature review of studies published in English language on the damage effects of N-acetyl-p-aminophenol in the kidneys, accessed through PubMed database.
Drug and Chemical Toxicology Downloaded from informahealthcare.com by Dalhousie University on 06/28/14 For personal use only.
Results Most frequently renal failure is known to appear after the toxic liver damage. The difference between these organs lie in the fact that the kidneys are significantly associated with bioactivation and toxicity depending on gender. In the renal and hepatic metabolism of the drug, the cytochrome P450 enzymes play a significant oxidizing role. CYP2E1 is the most important isoenzyme involved in the biotransformation of N-acetyl-p-aminophenol in the kidney and it may be induced via testosterone. It explains the variation in the metabolism and nephrotoxicity of N-acetyl-p-aminophenol dependent on the gender (Mazer & Perrone, 2008). It has been shown that the drug-induced nephrotoxicity occurred only in males and females mice with testosterone pretreatment. The lack of renal toxicity in female animal may suggest the androgen-dependent of renal CYP2E1 activity (Hoivik et al., 1995). It was also noted that CYP2E1 effected as a major catalyst in biotransformation of not only xenobiotics, but also endogenous substances, such as gender-dependent steroids. CYP2E1 activity induction mediated by androgen receptors seems to play an important role in cytochrome P450 expression (Kim et al., 2007; Henderson & Wolf, 1991). Androgen receptor complex can migrate to the nucleus and exert its effect on transcription. Probably, this process was not involved a direct interaction of androgen receptor with promoter in P450 genes (Henderson & Wolf, 1991). In other studies were shown that increased androgen level induced cytochrome P450 gene expression by acting either directly at the loci or thought a signaling pathway (Nakagawa et al., 2003). It was not excluded that in this process are involved others factors, such as kidney androgen regulated protein (Henderson & Wolf, 1991). It was believed that CYP2E1 mRNA contents can also be regulated at the posttranscriptional level (Kim et al., 2007). There are some studies indicating that nephropathy may occur early as a result of administration of lower doses than those that can induce hepatotoxicity (Das et al., 2010). Therefore, renal failure need not be exclusively the result coexisting with liver damage (Bessems & Vermeulen, 2001; Le Vaillant et al., 2013). Nephrotoxic effect depends on the time and dose of N-acetyl-p-aminophenol (Fored et al., 2001). However, the correlation between renal damage dose is not as obvious as in the case of liver damage (Mour et al., 2005). The effect of nephrotoxicity of N-acetyl-p-aminophenol can be explained thought other mechanisms, such as metabolism by prostaglandin endoperoxide synthase (PGES) and N-deacetylase (Bessems & Vermeulen, 2001). The pathogenesis of renal toxicity of N-acetyl-p-aminophenol is not clear (Cermik et al., 2013; Le Vaillant et al., 2013). It is supposed that nephrotoxicity is associated with a complex biochemical process, similar to that occurring in the
liver, which comprises oxidizing activity of cytochrome P450 enzymes (da Silva Melo et al., 2006; Hart et al., 1994). As a result of the action of cytochrome P450 enzymes, a very reactive metabolite N-acetyl-p-benzochinoimine (NAPQI) is formed. Probably oxidizing properties of NAPQI are associated with cellular metabolism, in which the metabolite is subjected to one-electron reduction and then re-oxidized. This process is accompanied by the production of free radicals (Cermik et al., 2013; Zhao et al., 2011). Under physiological conditions, NAPQI is combined with GSH and detoxified. When GSH concentration is too low, the metabolite can form a covalent bonds with renal proteins leading to their destruction (Abdel-Zaher et al., 2007; Das et al., 2010). In the presence of the existing hepatic toxicity precluding further biotransformation of N-acetyl-p-aminophenol, the metabolic functions to the kidneys are transferred (Boutis & Shannon, 2001). The consequence of the reduction in GSH concentration is the reduction in the NAPQI inactivation in renal tubules. This leads to the covalent binding of metabolite with macromolecules or abnormal cell homeostasis increasing toxic effect of NAPQI (da Silva Melo et al., 2006) (Figure 1). Incorporation of the reactive metabolite into macromolecules can lead to the initiation of lipid peroxidation, which may result in kidneys damage (Abdel-Zaher et al., 2007; Li et al., 2003). In this case, nephrotoxicity is diagnosed after hepatotoxicity. N-acetyl-p-aminophenol can be metabolized by the liver and kidney, with no clinical evidence of hepatotoxicity. In this case, nephrotoxicity occurs regardless of hepatotoxicity and depending on the efficiency of the renal biotransformation by the cytochrome P450 enzymes and GSH (Boutis & Shannon, 2001). The N-acetyl-p-aminophenol detoxification with cytochrome P450 enzymes may coexist with the drug detoxification involving the N-deacetylase. The N-acetyl-paminophenol deacetylation in the cytosol and microsomes of kidney cells was observed (Mazer & Perrone, 2008). The substrate for the N-deacetylase were NAPQI and N-acetyl-p-aminophenol. As a result of enzyme activity was the substrates transformation to oxidised form and the formation of p-aminophenol (PAP) – a major metabolite of N-acetyl-p-aminophenol present in urine (Bessems & Vermeulen, 2001). It was shown that PAP subjected the autoxidation to form p-benzoquinone (PBQI) in aqueous solution. PBQI is known to be a highly reactive metabolite, which can bind to GSH or other compounds with sulfhydryl groups causing cytotoxic effect (Abdul Hamid et al., 2012; Carpenter & Mudge, 1981) (Figure 1). Finally, as a result of the N-acetyl-p-aminophenol metabolism by N-deacetylase, the damage to the proximal tubules in the kidney was observed (Carpenter & Mudge, 1981). In the kidney, both deacetylation of N-acetyl-p-aminophenol to p-aminophenol and re-acetylation of PAP to N-acetyl-p-aminophenol were occured. N-acetyl-p-aminophenol and PAP can damage selectively the same nephron segments. The nephrotoxic action of PAP is not fully understood. It is believed that the main role in this process play the transport of this metabolite along the renal tubule. Probably, p-aminophenol is able to diffuse in a passive transport to tubular cells and then PAP is excreted in the urine (Carpenter & Mudge, 1981). This fact makes it the most
DOI: 10.3109/01480545.2014.928722
N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity
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Figure 1. Mechanism of N-acetyl-p-aminophenol-induced cytotoxicity in renal cells. PGES – prostaglandin endoperoxide synthase, NAPQI – N-acetyl-p-benzoquinone imine, GSH – glutathione, PAP – p-aminophenol, PBQI – p-benzoquinone.
likely mechanism of pathogenesis of analgesic nephropathy. In the cases of chronic treatment of N-acetyl-p-aminophenol, the damage can be seen more clearly in the distal than in the proximal nephron (Carpenter & Mudge, 1981). N-acetyl-p-aminophenol exerts acute and chronic nephrotoxic effects. Acute toxicity after ingestion of large doses (10–15 g) is characterized by necrosis and damage to the proximal tubule. A subclinical analgesic nephropathy induced by ingestion of N-acetyl-p-aminophenol at 500 mg/kg of body weight for 30 days in the rat was shown (Ahmed et al., 2003). However, the chronic ingestion of N-acetyl-p-aminophenol (500–1000 mg) resulted in analgesic nephropathy, which led to renal papillary necrosis and chronic interstitial nephritis with progressive renal failure (Blantz, 1996; Henrich, 1998). In other studies was found that the acute administration of N-acetyl-p-aminophenol decreases sodium excretion, but does not affect the flow rate of urine, urine osmolality and glomerular filtration rate (GRF). These results are inconsistent to previous studies on the effects of chronic use of N-acetyl-paminophenol, which were associated with a decrease in GFR, sodium excretion and urine osmolality and resulted in large quantity of excreted urine (Ahmed et al., 2003). It was shown that the metabolism of N-acetyl-p-aminophenol involving prostaglandin endoperoxide synthase was most important for chronic, rarely acute N-acetyl-p-aminophenol administration. PGES is an enzyme that catalyzes the conversion of N-acetyl-p-aminophenol to NAPQI through free radicals. This process is more pronounced in the core of the kidney, whereas cyt-P450 plays an important role in the renal cortex (Figure 2). Despite the differences in metabolism, the result is the same – a reactive compound is produced, which is bound to cellular proteins leading to cell death and
tissue necrosis. A relation between nephrotoxicity and chronic drug intake suggest that N-acetyl-p-aminophenol is bound to the catalytic center of PGES with high affinity, that even therapeutic doses lead to toxic metabolites production (Bessems & Vermeulen, 2001; Mazer & Perrone, 2008). It has been shown that other cause of the nephrotoxicity induced by action of N-acetyl-p-aminophenol metabolites is the induction of apoptosis. Although the N-acetyl-p-aminophenol can increase the expression of Fas receptor on the surface of apoptotic cells, the Fas receptor is not involved in apoptosis. However, inappropriate and excessive activation of the Fas receptor may imply many pathological states of the liver, but it has no effect on renal tubular epithelial cells (Lorz et al., 2004). It was shown that apoptosis of the cells is dependent on N-acetyl-p-aminophenol-induced activation of caspase-9, caspase-3 and caspase-12. The caspase activation by N-acetyl-p-aminophenol is not fully understood. It was shown that N-acetyl-p-aminophenol did not induce loss of mitochondrial transmembrane potential or release of the proapoptotic factors, such as cytochrome c and Smac/ DIABLO into the cytosol (Lorz et al., 2004). It was reported that N-acetyl-p-aminophenol-induced apoptosis involved activation of caspase-9 and caspase-3 in the absence of cytostolic factors. The abilities of caspase-9 and caspase-3 to cleaving antiapoptotic Bcl-xL protein into fragments with proapoptotic activity were observed. It was shown that decreased Bcl-xL protein level induced an increase in cytokines level, such as TNFa and TNF-induced apoptosis was initiated (Lorz et al., 2005). It was observed that N-acetyl-p-aminophenol induced endoplasmic reticulum stress in tubular epithelial cells. An increased N-acetyl-p-aminophenol level causing an increase in GADD153 – marker of endoplasmic reticulum stress, its
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Figure 2. The ways of metabolism of N-acetyl-p-aminophenol in different parts of the rabbit kidney; PGES – prostaglandin endoperoxide synthase, P450 – cytochrome P450 enzymes, NAPQI – N-acetyl-p-benzoquinone imine (Bessems & Vermeulen, 2001).
translocation to the nucleus and activation of caspase-12 or transcription factors inducing apoptosis were observed. N-acetyl-p-aminophenol-induced GADD153 translocation to the nucleus and caspase-12 activation play a key role in renal apoptosis induction (Lorz et al., 2004). The expression of caspase-12 activated by oxidative stress in tubular epithelial cells (but is not found in the glomerulus) suggests that they are particularly affected by the nephrotoxicity effect (Lorz et al., 2004). Therefore, it is assumed that the induction of apoptosis in renal tubular epithelial cells and not necrosis underlies the nephrotoxic potential of N-acetyl-p-aminophenol. It was reported that N-acetyl-p-aminophenol poisoning resulted in the acute renal tubular necrosis (Mazer & Perrone, 2008; Waring et al., 2010). The beginning kidney damage between the second and fifth day of drug abuse was observed, the peak serum creatinine between 3 and 16 day (average 7.3 days) was noted (Eguia & Materson, 1997). Kidney damage has occured with delay in relation to hepatic injury, since the peak serum creatinine approximately 3 days after the peak alanine aminotransferase concentrations (2.2–2.9 versus 4.4–5.9 days) was observed (Waring et al., 2010). Oliguria have been reported in 74% of patients with nephrotoxic effects of N-acetyl-p-aminophenol, while 42% of patients required renal replacement therapy (Eguia & Materson, 1997). It have been developed numerous and specific urine markers, which may be useful in the early detection of renal toxicity, e.g. g-glutamyl transferase (GGT), glutathione S-transferase (GST), N-acetylglucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, cystatin C and kidney injury molecule-1. It was shown an increased concentration of NAG, NAG isoenzyme B, b-galactosidase, a-GST, b-glucuronidase, GGT and b2-mikroglobulin in urine, what is important for diagnostic in N-acetyl-p-aminophenolinduced renal damage (Fuchs & Hewitt, 2011; Waring & Moonie, 2011).
There are reports that N-acetyl-p-aminophenol combinations with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) can enhance the nephrotoxicity in dosedependent manner (Kumar et al., 2010). In the ibuprofen and its combination groups, acute tubular necrosis in kidney was observed. Cystic degeneration in the ibuprofen (100 mg/kg) with N-acetyl-p-aminophenol (100 mg/kg) group was noted. Acute tubular necrosis was shown in celecoxib (30 mg/kg) group and celecoxib (20 mg/kg) with N-acetyl-p-aminophenol (100 mg/kg) group. Focal tubular cast in kidney in celecoxib combination group was shown. This toxicity might be due to synergistic or additive action of NSAIDs with N-acetyl-paminophenol. The renal histopathology was conducted to evaluate inflammation, tubular damage, papillary necrosis and interstitial changes (Kumar et al., 2010). In other study was found that N-acetyl-p-aminophenol (380 mg/kg of body weight) and aspirin (230 mg/kg of body weight) administrated for 21 weeks to female Fischer-344 rats resulted in papillary necrosis and impaired ability to concentrate urine, although a lower dose of N-acetyl-p-aminophenol alone (120 mg/kg of body weight) did not induce significant renal damage (Burrell et al., 1990). Histopathology of the kidneys affected by the toxic effects of N-acetyl-p-aminophenol exhibits acute tubular necrosis (ATN). The toxic metabolites of the drug can damage primarily the proximal tubule, but this injury can be extended. Renal failure due to N-acetyl-p-aminophenol metabolites is correlated with the presence of ATN (Mazer & Perrone, 2008). A variety of contributing factors, such as: chronic liver failure, gender or vulnerability to changes in the cyt-P450 enzymes activity may also affect on kidney damage (Blantz, 1996). In adults, renal failure after an overdose of N-acetyl-paminophenol usually leads to the development of hepatotoxicity. However, in adolescents the prevalence of nephrotoxicity is greater. The reason for these differences is not identified (Boutis & Shannon, 2001).
DOI: 10.3109/01480545.2014.928722
Conclusions
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The oxidizing effect of cytochrome P450 enzymes plays an essential role both in renal and hepatic metabolism of N-acetyl-p-aminophenol. As a result of the N-acetyl-paminophenol biotransformation, the reactive metabolites (NAPQI and PBQI) with the ability to produce a covalent bonds with sulfhydryl groups of proteins are formed. These metabolites increases the nephrotoxic effect of the drug. The formation of N-acetyl-p-aminophenol metabolites is associated with increased oxidative stress that promotes the kidneys damage. It is believed that in the pathogenesis of kidney damage a significant role plays the apoptosis of renal tubule epithelial cell.
Declaration of interest The authors report no declarations of interests.
References Abdel-Zaher AO, Abdel-Rahman MM, Hafez MM, Omran FM. (2007). Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage. Toxicology 234: 124–134. Abdul Hamid Z, Budin SB, Wen Jie N, et al. (2012). Nephroprotective effects of Zingiber zerumbet Smith ethyl acetate extract against paracetamol-induced nephrotoxicity and oxidative stress in rats. J Zhejiang Univ Sci B 13:176–185. Ahmed MH, Ashton N, Balment RJ. (2003). Renal function in a rat model of analgesic nephropathy: effect of chloroquine. J Pharmacol Exp Ther 305:123–130. Bessems JGM, Vermeulen NPE. (2001). Paracetamol (acetaminophen)induced toxicity: molekular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 31:55–138. Blantz RC. (1996). Acetaminophen: acute and chronic effects on renal function. Am J Kidney Dis 28:3–6. Boutis K, Shannon M. (2001). Nephrotoxicity after acute severe acetaminophen poisoning in adolescents. Clin Toxicol 39:441–445. Burrell JH, Yong JL, MacDonald GJ. (1990). Experimental analgesic nephropathy: changes in renal structure and urinary concentrating ability in Fischer 344 rats given continuous low doses of aspirin and paracetamol. Pathology 22:33–44. Carpenter HM, Mudge GH. (1981). Acetaminophen nephrotoxicity: studies on renal acetylation and deacetylation. Pharmacol Exp Therapeut 218:161–167. Cermik H, Taslipinar MY, Aydin I, et al. (2013). The relationship between N-acetylcysteine, hyperbaric oxygen, and inflammation in a rat model ofacetaminophen-induced nephrotoxicity. Inflammation 36: 1145–1152. Chandrasekharan NV, Dai H, Turepu Roos KL, et al. (2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci 99:13926–13931. da Silva Melo DA, Saciura VC, Poloni JAT, et al. (2006). Evaluation of renal enzymuria and cellular excretion as an marker of acute nephrotoxicity due to an overdose of paracetamol in Wistar rats. Clin Chim Acta 373:88–91. Das J, Ghosh J, Manna P, Sil PC. (2010). Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology 269:24–34. Duffull SB, Isbister GK. (2013). Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose. Clin Toxicol (Phila) 51:772–776.
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Eguia L, Materson BJ. (1997). Acetaminophen-related acute renal failure without fulminant liver failure. Pharmacotherapy 17: 363–370. Fored CM, Ejerblad E, Lindblad P, et al. (2001). Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 345:1801–1808. Fuchs TC, Hewitt P. (2011). Biomarkers for drug-induced renal damage and nephrotoxicity – an overview for applied toxicology. AAPS J 13: 615–631. Hart SGE, Beierschmitt WP, Wyand DS, et al. (1994). Acetaminophen nephrotoxicity in CD-1 mice, evidence of a role for in situ activation in selective covalent binding and toxicity. Toxicol Appl Pharmacol 126:267–275. Henderson CJ, Wolf CR. (1991). Evidence that the androgen receptor mediates sexual differentiation of mouse renal cytochrome P450 expression. Biochem J 278:499–503. Henrich WL. (1998). Analgesic nephropathy. Trans Am Clin Climatol Assoc 109:147–158. Herrero JL, Castellano I, Gomez-Martino JR, et al. (2001). Acute renal failure caused by paracetamol poisoning. Nefrologia 21:592–595. Hoivik DJ, Manautou JE, Tveit A, et al. (1995). Gender-related differences in susceptibility to acetaminophen-induced protein arylation and nephrotoxicity in the CD-1 mouse. Toxicol Appl Pharmacol 130:257–271. Kim YC, Yim HK, Jung YS, et al. (2007). Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: role of male sex hormone. Toxicol Appl Pharmacol 223:56–65. Kumar G, Hota D, Nahar Saikia U, Pandhi P. (2010). Evaluation of analgesic efficacy, gastrotoxicity and nephrotoxicity of fixed-dose combinations of nonselective, preferential and selective cyclooxygenase inhibitors with paracetamol in rats. Exp Toxicol Pathol 62: 653–662. Le Vaillant J, Pellerin L, Brouard J, Eckart P. (2013). Acetaminophen (paracetamol) causing renal failure: report on 3 pediatric cases. Arch Pediatr 20:650–653. Li C, Liu J, Saavedra JE, et al. (2003). The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced nephrotoxicity in mice. Toxicology 189:173–180. Lorz C, Justo P, Sanz A, et al. (2004). Paracetamol-induced renal tubular injury: a role for ER stress. J Am Soc Nephrol 15:380–389. Lorz C, Justo P, Sanz AB, et al. (2005). Role of Bcl-xL in paracetamolinduced tubular epithelial cell death. Kidney Int 67:592–601. Manchanda A, Cameron C, Robinson G. (2013). Beware of paracetamol use in alcohol abusers: a potential cause of acute liver injury. N Z Med J 126:80–84. Mazer M, Perrone J. (2008). Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestation and management. J Med Toxicol 4:2–6. McGill MR, Jaeschke H. (2013). Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res 30:2174–2187. Mour G, Feinfeld DA, Caraccio T, McGuigan M. (2005). Acute renal dysfunction in acetaminophen poisoning. Ren Fail 27: 381–383. Nakagawa K, Marji JS, Schwartzman ML, et al. (2003). Androgenmediated induction of the kidney arachidonate hydroxylases is associated with the development of hypertension. Am J Physiol Regul Integr Comp Physiol 284:1055–1062. Waring WS, Jamie H, Leggett GE. (2010). Delayed onset of acute renal failure after significant paracetamol overdose: a case series. Hum Exp Toxicol 29:63–68. Waring WS, Moonie A. (2011). Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury. Clin Toxicol (Phila) 49: 720–728. Zhao YL, Zhou GD, Yang HB, et al. (2011). Rhein protects against acetaminophen-induced hepatic and renal toxicity. Food Chem Toxicol 49:1705–1710.
REVIEW ARTICLE
Mechanisms of interaction of the N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity
Drug and Chemical Toxicology Downloaded from informahealthcare.com by Dalhousie University on 06/28/14 For personal use only.
Milena S´ciskalska, Mariola S´liwin´ska-Mosson´, Magdalena Podawacz, Waldemar Sajewicz, and Halina Milnerowicz Department of Biomedical and Environmental Analysis, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
Abstract
Keywords
Context: Epidemiological studies have demonstrated that chronic use of N-acetylp-aminophenol is correlated with the occurrence of renal dysfunction. Objective: Aim of this study was to review the literature on the mechanisms of interaction N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity. Methods: We present a literature review of studies published in English language on the damage effects of N-acetyl-p-aminophenol on the kidneys, accessed through PubMed database. Results: The pathogenesis of drug-induced nephrotoxicity attributed to the action of cytochrome P450 enzymes, prostaglandin endoperoxide synthase (PGES) and N-deacetylase. The metabolism of N-acetyl-p-aminophenol with the participation of PGES more explicit is in the core of kidney, whereas cytochrome P450 enzymes play role in the renal cortex. Due to the action of cytochrome P450 and N-deacetylase, a very reactive N-acetyl-p-benzochinoimine (NAPQI) is formed. The result of the catalytic activity of PGES is p-benzoquinone (PBQI) production. The formation of NAPQI and PBQI is accompanied by the production of free radicals. Metabolites can connect covalently with sulfhydryl groups of renal proteins, what can cause the injury of proximal tubules. N-acetyl-p-aminophenol may initiate the apoptosis process involving activation of caspase-9 and caspase-3, but also caspase-12 as a result of generation of free radicals. Conclusions: The process of NAPQI and PBQI formation can increase oxidative stress that promotes the kidneys damage. The ability of metabolites to produce covalent bonds with sulfhydryl groups of proteins can increase the nephrotoxicity. It was assumed that the induction of apoptosis in renal tubular epithelial cells, and not necrosis underlies the nephrotoxic potential of N-acetyl-p-aminophenol.
Cytochrome P450, N-acetyl-p-aminophenol, N-acetyl-p-benzochinoimine
Introduction N-acetyl-p-aminophenol is the drug derived from the group of non-narcotic analgesic and antipyretic drug for the treatment of mild-to-moderate pain (Chandrasekharan et al., 2002). It is a common ingredient in many over-the-counter analgesics, which promotes rapid overdose and numerous cases of poisoning. The risk of poisoning in human can be enhanced, while hepatic enzymes activities involved in N-acetylp-aminophenol metabolism are reduced, e.g. UDP-glucuronosyl transferases deficient in Gilbert’s syndrome (McGill & Jaeschke, 2013). The risk of N-acetyl-p-aminophenol poisoning is increased during chronic alcohol consumption, which can induce a metabolic activation of N-acetyl-p-aminophenol to harmful metabolites. However, acute alcohol exposure can reduce a liver injury, what is controversial (Manchanda et al., 2013; McGill & Jaeschke, 2013). Likewise, isoniasyd can
Address for correspondence: Milena S´ciskalska, Department of Biomedical and Environmental Analysis, Wroclaw Medical University, 211 Borowska St., 50-556 Wrocław, Poland. Tel: (0 71) 784 01 78. Tel/Fax: (0 71) 784 01 72. E-mail: [email protected]
History Received 12 February 2014 Revised 20 May 2014 Accepted 23 May 2014 Published online 24 June 2014
enhance or inhibit N-acetyl-p-aminophenol metabolism in dose-dependent manner (McGill & Jaeschke, 2013). These substances can be a risk factors for N-acetyl-p-aminophenol poisoning, because can intensify the effect of therapeutic dose, which may became a toxic dose. N-acetyl-p-aminophenol overdose remains one of the most important common poisonings in many parts of the world (Duffull & Isbister, 2013). In the United States, N-acetyl-paminophenol overdose is responsible for 50-80 000 emergency department visits each year, 26 000 hospitalizations and 500 deaths (McGill & Jaeschke, 2013). A toxic dose of N-acetyl-p-aminophenol is not known. Toxic dose is defined empirically as a dose that is known to cause toxicity. Various guidelines suggest different toxic doses. Most international guidelines recommend 200 mg/kg of body weight or 10 g as a toxic dose (Duffull & Isbister, 2013). Especially often dangerous complication of the N-acetyl-p-aminophenol overdose is liver damage (Cermik et al., 2013). However, chronic use of N-acetyl-p-aminophenol correlating with renal dysfunction in epidemiological studies were shown (Herrero et al., 2001; Le Vaillant et al., 2013). The aim of this study was to review the literature on the mechanisms of interaction
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M. S´ciskalska et al.
N-acetyl-p-aminophenol nephrotoxicity.
Drug Chem Toxicol, Early Online: 1–5
metabolites
in
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Materials and methods We present a literature review of studies published in English language on the damage effects of N-acetyl-p-aminophenol in the kidneys, accessed through PubMed database.
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Results Most frequently renal failure is known to appear after the toxic liver damage. The difference between these organs lie in the fact that the kidneys are significantly associated with bioactivation and toxicity depending on gender. In the renal and hepatic metabolism of the drug, the cytochrome P450 enzymes play a significant oxidizing role. CYP2E1 is the most important isoenzyme involved in the biotransformation of N-acetyl-p-aminophenol in the kidney and it may be induced via testosterone. It explains the variation in the metabolism and nephrotoxicity of N-acetyl-p-aminophenol dependent on the gender (Mazer & Perrone, 2008). It has been shown that the drug-induced nephrotoxicity occurred only in males and females mice with testosterone pretreatment. The lack of renal toxicity in female animal may suggest the androgen-dependent of renal CYP2E1 activity (Hoivik et al., 1995). It was also noted that CYP2E1 effected as a major catalyst in biotransformation of not only xenobiotics, but also endogenous substances, such as gender-dependent steroids. CYP2E1 activity induction mediated by androgen receptors seems to play an important role in cytochrome P450 expression (Kim et al., 2007; Henderson & Wolf, 1991). Androgen receptor complex can migrate to the nucleus and exert its effect on transcription. Probably, this process was not involved a direct interaction of androgen receptor with promoter in P450 genes (Henderson & Wolf, 1991). In other studies were shown that increased androgen level induced cytochrome P450 gene expression by acting either directly at the loci or thought a signaling pathway (Nakagawa et al., 2003). It was not excluded that in this process are involved others factors, such as kidney androgen regulated protein (Henderson & Wolf, 1991). It was believed that CYP2E1 mRNA contents can also be regulated at the posttranscriptional level (Kim et al., 2007). There are some studies indicating that nephropathy may occur early as a result of administration of lower doses than those that can induce hepatotoxicity (Das et al., 2010). Therefore, renal failure need not be exclusively the result coexisting with liver damage (Bessems & Vermeulen, 2001; Le Vaillant et al., 2013). Nephrotoxic effect depends on the time and dose of N-acetyl-p-aminophenol (Fored et al., 2001). However, the correlation between renal damage dose is not as obvious as in the case of liver damage (Mour et al., 2005). The effect of nephrotoxicity of N-acetyl-p-aminophenol can be explained thought other mechanisms, such as metabolism by prostaglandin endoperoxide synthase (PGES) and N-deacetylase (Bessems & Vermeulen, 2001). The pathogenesis of renal toxicity of N-acetyl-p-aminophenol is not clear (Cermik et al., 2013; Le Vaillant et al., 2013). It is supposed that nephrotoxicity is associated with a complex biochemical process, similar to that occurring in the
liver, which comprises oxidizing activity of cytochrome P450 enzymes (da Silva Melo et al., 2006; Hart et al., 1994). As a result of the action of cytochrome P450 enzymes, a very reactive metabolite N-acetyl-p-benzochinoimine (NAPQI) is formed. Probably oxidizing properties of NAPQI are associated with cellular metabolism, in which the metabolite is subjected to one-electron reduction and then re-oxidized. This process is accompanied by the production of free radicals (Cermik et al., 2013; Zhao et al., 2011). Under physiological conditions, NAPQI is combined with GSH and detoxified. When GSH concentration is too low, the metabolite can form a covalent bonds with renal proteins leading to their destruction (Abdel-Zaher et al., 2007; Das et al., 2010). In the presence of the existing hepatic toxicity precluding further biotransformation of N-acetyl-p-aminophenol, the metabolic functions to the kidneys are transferred (Boutis & Shannon, 2001). The consequence of the reduction in GSH concentration is the reduction in the NAPQI inactivation in renal tubules. This leads to the covalent binding of metabolite with macromolecules or abnormal cell homeostasis increasing toxic effect of NAPQI (da Silva Melo et al., 2006) (Figure 1). Incorporation of the reactive metabolite into macromolecules can lead to the initiation of lipid peroxidation, which may result in kidneys damage (Abdel-Zaher et al., 2007; Li et al., 2003). In this case, nephrotoxicity is diagnosed after hepatotoxicity. N-acetyl-p-aminophenol can be metabolized by the liver and kidney, with no clinical evidence of hepatotoxicity. In this case, nephrotoxicity occurs regardless of hepatotoxicity and depending on the efficiency of the renal biotransformation by the cytochrome P450 enzymes and GSH (Boutis & Shannon, 2001). The N-acetyl-p-aminophenol detoxification with cytochrome P450 enzymes may coexist with the drug detoxification involving the N-deacetylase. The N-acetyl-paminophenol deacetylation in the cytosol and microsomes of kidney cells was observed (Mazer & Perrone, 2008). The substrate for the N-deacetylase were NAPQI and N-acetyl-p-aminophenol. As a result of enzyme activity was the substrates transformation to oxidised form and the formation of p-aminophenol (PAP) – a major metabolite of N-acetyl-p-aminophenol present in urine (Bessems & Vermeulen, 2001). It was shown that PAP subjected the autoxidation to form p-benzoquinone (PBQI) in aqueous solution. PBQI is known to be a highly reactive metabolite, which can bind to GSH or other compounds with sulfhydryl groups causing cytotoxic effect (Abdul Hamid et al., 2012; Carpenter & Mudge, 1981) (Figure 1). Finally, as a result of the N-acetyl-p-aminophenol metabolism by N-deacetylase, the damage to the proximal tubules in the kidney was observed (Carpenter & Mudge, 1981). In the kidney, both deacetylation of N-acetyl-p-aminophenol to p-aminophenol and re-acetylation of PAP to N-acetyl-p-aminophenol were occured. N-acetyl-p-aminophenol and PAP can damage selectively the same nephron segments. The nephrotoxic action of PAP is not fully understood. It is believed that the main role in this process play the transport of this metabolite along the renal tubule. Probably, p-aminophenol is able to diffuse in a passive transport to tubular cells and then PAP is excreted in the urine (Carpenter & Mudge, 1981). This fact makes it the most
DOI: 10.3109/01480545.2014.928722
N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity
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Figure 1. Mechanism of N-acetyl-p-aminophenol-induced cytotoxicity in renal cells. PGES – prostaglandin endoperoxide synthase, NAPQI – N-acetyl-p-benzoquinone imine, GSH – glutathione, PAP – p-aminophenol, PBQI – p-benzoquinone.
likely mechanism of pathogenesis of analgesic nephropathy. In the cases of chronic treatment of N-acetyl-p-aminophenol, the damage can be seen more clearly in the distal than in the proximal nephron (Carpenter & Mudge, 1981). N-acetyl-p-aminophenol exerts acute and chronic nephrotoxic effects. Acute toxicity after ingestion of large doses (10–15 g) is characterized by necrosis and damage to the proximal tubule. A subclinical analgesic nephropathy induced by ingestion of N-acetyl-p-aminophenol at 500 mg/kg of body weight for 30 days in the rat was shown (Ahmed et al., 2003). However, the chronic ingestion of N-acetyl-p-aminophenol (500–1000 mg) resulted in analgesic nephropathy, which led to renal papillary necrosis and chronic interstitial nephritis with progressive renal failure (Blantz, 1996; Henrich, 1998). In other studies was found that the acute administration of N-acetyl-p-aminophenol decreases sodium excretion, but does not affect the flow rate of urine, urine osmolality and glomerular filtration rate (GRF). These results are inconsistent to previous studies on the effects of chronic use of N-acetyl-paminophenol, which were associated with a decrease in GFR, sodium excretion and urine osmolality and resulted in large quantity of excreted urine (Ahmed et al., 2003). It was shown that the metabolism of N-acetyl-p-aminophenol involving prostaglandin endoperoxide synthase was most important for chronic, rarely acute N-acetyl-p-aminophenol administration. PGES is an enzyme that catalyzes the conversion of N-acetyl-p-aminophenol to NAPQI through free radicals. This process is more pronounced in the core of the kidney, whereas cyt-P450 plays an important role in the renal cortex (Figure 2). Despite the differences in metabolism, the result is the same – a reactive compound is produced, which is bound to cellular proteins leading to cell death and
tissue necrosis. A relation between nephrotoxicity and chronic drug intake suggest that N-acetyl-p-aminophenol is bound to the catalytic center of PGES with high affinity, that even therapeutic doses lead to toxic metabolites production (Bessems & Vermeulen, 2001; Mazer & Perrone, 2008). It has been shown that other cause of the nephrotoxicity induced by action of N-acetyl-p-aminophenol metabolites is the induction of apoptosis. Although the N-acetyl-p-aminophenol can increase the expression of Fas receptor on the surface of apoptotic cells, the Fas receptor is not involved in apoptosis. However, inappropriate and excessive activation of the Fas receptor may imply many pathological states of the liver, but it has no effect on renal tubular epithelial cells (Lorz et al., 2004). It was shown that apoptosis of the cells is dependent on N-acetyl-p-aminophenol-induced activation of caspase-9, caspase-3 and caspase-12. The caspase activation by N-acetyl-p-aminophenol is not fully understood. It was shown that N-acetyl-p-aminophenol did not induce loss of mitochondrial transmembrane potential or release of the proapoptotic factors, such as cytochrome c and Smac/ DIABLO into the cytosol (Lorz et al., 2004). It was reported that N-acetyl-p-aminophenol-induced apoptosis involved activation of caspase-9 and caspase-3 in the absence of cytostolic factors. The abilities of caspase-9 and caspase-3 to cleaving antiapoptotic Bcl-xL protein into fragments with proapoptotic activity were observed. It was shown that decreased Bcl-xL protein level induced an increase in cytokines level, such as TNFa and TNF-induced apoptosis was initiated (Lorz et al., 2005). It was observed that N-acetyl-p-aminophenol induced endoplasmic reticulum stress in tubular epithelial cells. An increased N-acetyl-p-aminophenol level causing an increase in GADD153 – marker of endoplasmic reticulum stress, its
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Figure 2. The ways of metabolism of N-acetyl-p-aminophenol in different parts of the rabbit kidney; PGES – prostaglandin endoperoxide synthase, P450 – cytochrome P450 enzymes, NAPQI – N-acetyl-p-benzoquinone imine (Bessems & Vermeulen, 2001).
translocation to the nucleus and activation of caspase-12 or transcription factors inducing apoptosis were observed. N-acetyl-p-aminophenol-induced GADD153 translocation to the nucleus and caspase-12 activation play a key role in renal apoptosis induction (Lorz et al., 2004). The expression of caspase-12 activated by oxidative stress in tubular epithelial cells (but is not found in the glomerulus) suggests that they are particularly affected by the nephrotoxicity effect (Lorz et al., 2004). Therefore, it is assumed that the induction of apoptosis in renal tubular epithelial cells and not necrosis underlies the nephrotoxic potential of N-acetyl-p-aminophenol. It was reported that N-acetyl-p-aminophenol poisoning resulted in the acute renal tubular necrosis (Mazer & Perrone, 2008; Waring et al., 2010). The beginning kidney damage between the second and fifth day of drug abuse was observed, the peak serum creatinine between 3 and 16 day (average 7.3 days) was noted (Eguia & Materson, 1997). Kidney damage has occured with delay in relation to hepatic injury, since the peak serum creatinine approximately 3 days after the peak alanine aminotransferase concentrations (2.2–2.9 versus 4.4–5.9 days) was observed (Waring et al., 2010). Oliguria have been reported in 74% of patients with nephrotoxic effects of N-acetyl-p-aminophenol, while 42% of patients required renal replacement therapy (Eguia & Materson, 1997). It have been developed numerous and specific urine markers, which may be useful in the early detection of renal toxicity, e.g. g-glutamyl transferase (GGT), glutathione S-transferase (GST), N-acetylglucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, cystatin C and kidney injury molecule-1. It was shown an increased concentration of NAG, NAG isoenzyme B, b-galactosidase, a-GST, b-glucuronidase, GGT and b2-mikroglobulin in urine, what is important for diagnostic in N-acetyl-p-aminophenolinduced renal damage (Fuchs & Hewitt, 2011; Waring & Moonie, 2011).
There are reports that N-acetyl-p-aminophenol combinations with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) can enhance the nephrotoxicity in dosedependent manner (Kumar et al., 2010). In the ibuprofen and its combination groups, acute tubular necrosis in kidney was observed. Cystic degeneration in the ibuprofen (100 mg/kg) with N-acetyl-p-aminophenol (100 mg/kg) group was noted. Acute tubular necrosis was shown in celecoxib (30 mg/kg) group and celecoxib (20 mg/kg) with N-acetyl-p-aminophenol (100 mg/kg) group. Focal tubular cast in kidney in celecoxib combination group was shown. This toxicity might be due to synergistic or additive action of NSAIDs with N-acetyl-paminophenol. The renal histopathology was conducted to evaluate inflammation, tubular damage, papillary necrosis and interstitial changes (Kumar et al., 2010). In other study was found that N-acetyl-p-aminophenol (380 mg/kg of body weight) and aspirin (230 mg/kg of body weight) administrated for 21 weeks to female Fischer-344 rats resulted in papillary necrosis and impaired ability to concentrate urine, although a lower dose of N-acetyl-p-aminophenol alone (120 mg/kg of body weight) did not induce significant renal damage (Burrell et al., 1990). Histopathology of the kidneys affected by the toxic effects of N-acetyl-p-aminophenol exhibits acute tubular necrosis (ATN). The toxic metabolites of the drug can damage primarily the proximal tubule, but this injury can be extended. Renal failure due to N-acetyl-p-aminophenol metabolites is correlated with the presence of ATN (Mazer & Perrone, 2008). A variety of contributing factors, such as: chronic liver failure, gender or vulnerability to changes in the cyt-P450 enzymes activity may also affect on kidney damage (Blantz, 1996). In adults, renal failure after an overdose of N-acetyl-paminophenol usually leads to the development of hepatotoxicity. However, in adolescents the prevalence of nephrotoxicity is greater. The reason for these differences is not identified (Boutis & Shannon, 2001).
DOI: 10.3109/01480545.2014.928722
Conclusions
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The oxidizing effect of cytochrome P450 enzymes plays an essential role both in renal and hepatic metabolism of N-acetyl-p-aminophenol. As a result of the N-acetyl-paminophenol biotransformation, the reactive metabolites (NAPQI and PBQI) with the ability to produce a covalent bonds with sulfhydryl groups of proteins are formed. These metabolites increases the nephrotoxic effect of the drug. The formation of N-acetyl-p-aminophenol metabolites is associated with increased oxidative stress that promotes the kidneys damage. It is believed that in the pathogenesis of kidney damage a significant role plays the apoptosis of renal tubule epithelial cell.
Declaration of interest The authors report no declarations of interests.
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