Covalent Modification of Rat Liver Dipeptidyl Peptidase IV (CD26) by the Nonsteroidal Anti-Inflammatory Drug Diclofenac

Hargus, Sally J.; Martin, Brian M.; George, John W.; Pohl, Lance R.

doi:10.1021/tx00050a001

Cited by 85 publications

(43 citation statements)

References 22 publications

(27 reference statements)

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“…Boelsterli (2003) also described the occurrence of DCF acyl-glucuronids in humans and experimental animals, which remain reactive and can lead to protein adducts unless scavenged by glutathion. In trout, DCF is possibly also partially excreted as reactive DCF acyl-glucuronide via the kidney, where it could provide for protein adducts, as has been described previously in the liver where these adducts are considered causal in the observed idiosyncratic hepatotoxicity (Kretz-Rommel and Boelsterli, 1994;Hargus et al, 1994Hargus et al, , 1995. The formation of DCF-protein adducts may also be responsible for kidney pathology described for DCF exposed humans and fish (Hickey et al, 2001;Oaks et al, 2004;Risebrough, 2004;Schwaiger et al, 2004).…”

Section: Discussionmentioning

confidence: 66%

Distribution of intraperitoneally injected diclofenac in brown trout (Salmo trutta f. fario)

Hoeger

Dietrich

Schmid

et al. 2008

Ecotoxicology and Environmental Safety

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The detection of low levels of pharmaceuticals in aquatic environments has lately raised concerns regarding possible adverse effects of these highly active substances on aquatic organisms. The non steroidal anti inflammatory drug diclofenac (DCF) is one of the pharmaceutical substances regularly detected in surface waters and has lately been demonstrated to elicit adverse effects in salmonid species at environmentally relevant concentrations. The aim of the present study was to investigate the distribution of DCF in indigenous brown trout (Salmo trutta f. fario) following intraperitoneal (i.p.) injection of a single dose of 14 C labelled DCF. A distribution kinetic over 36 h provides information on possible accumulation of DCF in different organs as well as on DCF detoxification in trout, possibly enabling identification of sites of preferential toxicity. Approximately 57% of the total single DCF dose appeared in the bile 6 h after i.p. application. Subsequently, DCF was observed to undergo enterohepatic cycling with an amount of 14 C activity comparable to the 6 h bile values reappearing in bile 36 h after application. Results for 14 C activity in intestine and pylori support the observation of enterohepatic cycling with a small peak in intestine at 3 h post i.p. injection and a low peak in intestine and pylori at 6 h post i.p. injection, reflecting presence of the drug substance in bile. The highest activity in intestine was found 24 h post injection coinciding with low levels in bile, followed by a gradual decrease of activity in intestine mirroring the re uptake of DCF into bile. The finding of enterohepatic cycling of DCF in brown trout is suggestive of a prolonged retention of DCF in brown trout.

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Section: Discussionmentioning

confidence: 66%

Distribution of intraperitoneally injected diclofenac in brown trout (Salmo trutta f. fario)

Hoeger

Dietrich

Schmid

et al. 2008

Ecotoxicology and Environmental Safety

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“…Although diclofenac was shown to bind irreversibly to hepatic microsomal proteins in several studies (Kretz‐Rommel and Boelsterli 1994; Hargus et al. 1995; Obach et al. 2008), the targeted polypeptides are still unidentified.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

189

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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“…DCF-AG undergoes these rearrangements as the pH changes from acidic to physiologic conditions such as those that occur in the GI tract (Ebner et al, 1999;Kenny et al, 2004). DCF-AG can form adducts with multiple proteins in the liver and GI tract, and dipeptidyl peptidase IV was identified as a DCF-AG target in rat liver, where adduction resulted in decreased activity (Hargus et al, 1995). Furthermore, it was found that broadacting UGT inhibitors can significantly diminish the covalent binding of DCF metabolite to hepatocellular proteins in vitro (Kretz-Rommel and Boelsterli, 1993).…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug commonly prescribed to reduce pain in acute and chronic inflammatory diseases. One of the main DCF metabolites is a reactive diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets and may contribute to adverse drug reactions arising from DCF use. Cellular efflux of DCF-AG is partially mediated by multidrug resistanceassociated proteins (Mrp). The importance of Mrp2 during DCFinduced toxicity has been established, yet the role of Mrp3 remains largely unexplored. In the present work, Mrp3-null (KO) mice were used to study the toxicokinetics and toxicodynamics of DCF and its metabolites. DCF-AG plasma concentrations were 90% lower in KO mice than in wild-type (WT) mice, indicating that Mrp3 mediates DCF-AG basolateral efflux. In contrast, there were no differences in DCF-AG biliary excretion between WT and KO, suggesting that only DCF-AG basolateral efflux is compromised by Mrp3 deletion. Susceptibility to toxicity was also evaluated after a single high DCF dose. No signs of injury were detected in livers and kidneys; however, ulcers were found in the small intestines. Furthermore, the observed intestinal injuries were consistently more severe in KO compared with WT. DCF covalent adducts were observed in liver and small intestines; however, staining intensity did not correlate with the severity of injuries, implying that tissues respond differently to covalent modification. Overall, the data provide strong evidence that (1) in vivo Mrp3 plays an important role in DCF-AG disposition and (2) compromised Mrp3 function can enhance injury in the gastrointestinal tract after DCF treatment.

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Covalent Modification of Rat Liver Dipeptidyl Peptidase IV (CD26) by the Nonsteroidal Anti-Inflammatory Drug Diclofenac

Cited by 85 publications

References 22 publications

Distribution of intraperitoneally injected diclofenac in brown trout (Salmo trutta f. fario)

Distribution of intraperitoneally injected diclofenac in brown trout (Salmo trutta f. fario)

Role of endoplasmic reticulum stress in drug‐induced toxicity

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

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