Cholestasis induced nephrotoxicity: The role of endogenous opioids

Deroee, Armin Farajzadeh; Nezami, Behtash Ghazi; Mehr, Shahram Ejtemaei; Hosseini, Reshad; Salmasi, Amirali; Talab, Saman Shafaat; Jahanzad, Issa; Dehpour, Ahmad Reza

doi:10.1016/j.lfs.2010.02.005

Cited by 10 publications

(5 citation statements)

References 46 publications

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“…NAG is a lysosomal enzyme of the proximal tubule epithelial cells; due to its large molecular weight, it is not filtered through the glomerulus, and is neither absorbed nor secreted by renal tubules. Unlike other renal function biomarkers that are filtered through the glomerulus, increased urine levels of NAG, deriving exclusively from tubule cells, specifically reflect proximal tubule dysfunction [ 142 , 182 , 183 , 184 , 185 , 186 ]. NAG has been suggested as a more sensitive biomarker of early nephropathy than albuminuria [ 185 , 186 ].…”

Section: Discussionmentioning

confidence: 99%

“…NAG has been suggested as a more sensitive biomarker of early nephropathy than albuminuria [ 185 , 186 ]. Interestingly, increased urinary NAG activity, as well as renal morphologic changes, were found in cholestatic rats and reversed by naltrexone treatment, suggesting the involvement of endogenous opioids in cholestatic nephrotoxicity [ 183 ]. Since our data are compatible with biliary obstruction, the hypothesis of exogenous opioid-induced cholestatic nephrotoxicity could be considered.…”

Section: Discussionmentioning

confidence: 99%

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Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

et al. 2020

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Tramadol and tapentadol are fully synthetic and extensively used analgesic opioids, presenting enhanced therapeutic and safety profiles as compared with their peers. However, reports of adverse reactions, intoxications and fatalities have been increasing. Information regarding the molecular, biochemical, and histological alterations underlying their toxicological potential is missing, particularly for tapentadol, owing to its more recent market authorization. Considering the paramount importance of liver and kidney for the metabolism and excretion of both opioids, these organs are especially susceptible to toxicological damage. In the present study, we aimed to characterize the putative hepatic and renal deleterious effects of repeated exposure to therapeutic doses of tramadol and tapentadol, using an in vivo animal model. Male Wistar rats were randomly divided into six experimental groups, composed of six animals each, which received daily single intraperitoneal injections of 10, 25 or 50 mg/kg tramadol or tapentadol (a low, standard analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively). An additional control group was injected with normal saline. Following 14 consecutive days of administration, serum, urine and liver and kidney tissue samples were processed for biochemical, metabolic and histological analysis. Repeated administration of therapeutic doses of both opioids led to: (i) increased lipid and protein oxidation in liver and kidney, as well as to decreased total liver antioxidant capacity; (ii) decreased serum albumin, urea, butyrylcholinesterase and complement C3 and C4 levels, denoting liver synthesis impairment; (iii) elevated serum activity of liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase, as well as lipid profile alterations, also reflecting hepatobiliary commitment; (iv) derangement of iron metabolism, as shown through increases in serum iron, ferritin, haptoglobin and heme oxygenase-1 levels. In turn, elevated serum cystatin C, decreased urine creatinine output and increased urine microalbumin levels were detected upon exposure to tapentadol only, while increased serum amylase and urine N-acetyl-β-D-glucosaminidase activities were observed for both opioids. Collectively, these results are compatible with kidney injury. Changes were also found in the expression levels of liver- and kidney-specific toxicity biomarker genes, upon exposure to tramadol and tapentadol, correlating well with alterations in lipid profile, iron metabolism and glomerular and tubular function. Histopathological analysis evidenced sinusoidal dilatation, microsteatosis, mononuclear cell infiltrates, glomerular and tubular disorganization, and increased Bowman’s spaces. Although some findings are more pronounced upon tapentadol exposure, our study shows that, when compared with acute exposure, prolonged administration of both opioids smooths the differences between their toxicological effects, and that these occur at lower doses within the therapeutic range.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

et al. 2020

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“…The incidences of rhabdomyolysis and ARF have been observed in heroin addict patients [18,49]. More recently, naltrexone treatment has been shown to produce significant changes in urinary N‐acetyl‐beta‐ d ‐glucosaminidase (NAG) as an early marker of renal tubular injury and renal morphology of cholestatic rats, thus suggesting a possible role of endogenous opioids in inducing cholestatic nephrotoxicity [50].…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of endogenous opioids and K_ATP channels in glycerol‐induced acute renal failure

Sauriyal

Jaggi

Singh³

et al. 2011

Fundamemntal Clinical Pharma

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The present study was designed to investigate the possible role of endogenous opioids and K(ATP) channels in glycerol-induced acute renal failure (ARF) in rats. The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 mL/kg), and the animals were sacrificed after 24 h of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury. Naltrexone (2.5, 5.0 and 10.0 mg/kg s.c.), glibenclamide (5.0 and 10.0 mg/kg i.p.), and minoxidil (25 and 50 mg/kg) were employed to explore the role of endogenous opioids and K(ATP) channels in rhabdomyolysis-induced ARF. Pretreatment with naltrexone and glibenclamide attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner, suggesting the role of endogenous opioids and K(ATP) channels in the pathogenesis of myoglobuniric renal failure. However, the simultaneous pretreatment with naltrexone (10 mg/kg s.c.) and glibenclamide (10 mg/kg i.p.) did not enhance the reno-protective effects of individual drugs, suggesting that release of endogenous opioids and opening of K(ATP) channels constitute a single pathway in acute renal injury triggered by hypertonic glycerol-induced rhabdomyolysis. Furthermore, administration of minoxidil abolished the attenuating effects of naltrexone in glycerol-induced renal failure, suggesting that opening of K(ATP) channels is downstream to opioid receptor activation. It is concluded that hypertonic glycerol-induced rhabdomyolysis may involve release of endogenous opioids that in turn modulate K(ATP) channels to contribute in the pathogenesis of ARF.

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“…Recently, Deroee and co-workers described the critical role of endogenous opioids in an experimental model of cholestasis (bile duct ligation)-induced renal failure in rats. Naltrexone treatment was shown to significantly reverse bile duct ligation-induced increased biochemical parameters of liver injury (alanine aminotransferase and aspartate transaminase) and renal injury (N-acetyl-β-D-glucosaminidase activity) along with prevention of structural alterations in renal tubules [38]. …”

Section: Endogenous Opioids and Renal Toxicitymentioning

confidence: 99%

A Review on Renal Toxicity Profile of Common Abusive Drugs

Singh

Jaggi

2013

Korean J Physiol Pharmacol

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Drug abuse has become a major social problem of the modern world and majority of these abusive drugs or their metabolites are excreted through the kidneys and, thus, the renal complications of these drugs are very common. Morphine, heroin, cocaine, nicotine and alcohol are the most commonly abused drugs, and their use is associated with various types of renal toxicity. The renal complications include a wide range of glomerular, interstitial and vascular diseases leading to acute or chronic renal failure. The present review discusses the renal toxicity profile and possible mechanisms of commonly abused drugs including morphine, heroin, cocaine, nicotine, caffeine and alcohol.

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Cholestasis induced nephrotoxicity: The role of endogenous opioids

Cited by 10 publications

References 46 publications

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

Investigating the role of endogenous opioids and K_ATP channels in glycerol‐induced acute renal failure

A Review on Renal Toxicity Profile of Common Abusive Drugs

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Cholestasis induced nephrotoxicity: The role of endogenous opioids

Cited by 10 publications

References 46 publications

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

Investigating the role of endogenous opioids and KATP channels in glycerol‐induced acute renal failure

A Review on Renal Toxicity Profile of Common Abusive Drugs

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Investigating the role of endogenous opioids and K_ATP channels in glycerol‐induced acute renal failure