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Research ArticleToxicology

Elucidation of the Mechanisms through Which the Reactive Metabolite Diclofenac Acyl Glucuronide Can Mediate Toxicity

Renato J. Scialis and José E. Manautou
Journal of Pharmacology and Experimental Therapeutics April 2016, 357 (1) 167-176; DOI: https://doi.org/10.1124/jpet.115.230755
Renato J. Scialis
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
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José E. Manautou
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
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Abstract

We have previously reported that mice lacking the efflux transporter Mrp3 had significant intestinal injury after toxic diclofenac (DCF) challenge, and proposed that diclofenac acyl glucuronide (DCF-AG), as a substrate of Mrp3, played a part in mediating injury. Since both humans and mice express the uptake transporter OATP2B1 in the intestines, OATP2B1 was characterized for DCF-AG uptake. In vitro assays using human embryonic kidney (HEK)-OATP2B1 cells demonstrated that DCF-AG was a substrate with a maximal velocity (Vmax) and Km of 17.6 ± 1.5 pmol/min per milligram and 14.3 ± 0.1 μM, respectively. Another key finding from our in vitro assays was that DCF-AG was more cytotoxic compared with DCF, and toxicity occurred within 1–3 hours of exposure. We also report that 1 mM DCF-AG caused a 6-fold increase in reactive oxygen species (ROS) by 3 hours. Investigation of oxidative stress through inhibition of superoxide dismutase (SOD) revealed that DCF-AG had 100% inhibition of SOD at the highest tested dose of 1 mM. The SOD and ROS results strongly suggest DCF-AG induced oxidative stress in vitro. Lastly, DCF-AG was screened for pharmacologic activity against COX-1 and COX-2 and was found to have IC50 values of 0.620 ± 0.105 and 2.91 ± 0.36 μM, respectively, which represents a novel finding. Since cyclooxygenase (COX) inhibition can lead to intestinal ulceration, it is plausible that DCF-AG can also contribute to enteropathy via COX inhibition. Taken in context, the work presented herein demonstrated the multifactorial pathways by which DCF-AG can act as a direct contributor to toxicity following DCF administration.

Footnotes

    • Received November 15, 2015.
    • Accepted February 10, 2016.
  • This work was supported by the National Institutes of Health [Grant DK069557].

  • dx.doi.org/ 10.1124/jpet.115.230755.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 357 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 357, Issue 1
1 Apr 2016
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Research ArticleToxicology

Mechanisms of Toxicity Caused by Diclofenac Acyl Glucuronide

Renato J. Scialis and José E. Manautou
Journal of Pharmacology and Experimental Therapeutics April 1, 2016, 357 (1) 167-176; DOI: https://doi.org/10.1124/jpet.115.230755

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Research ArticleToxicology

Mechanisms of Toxicity Caused by Diclofenac Acyl Glucuronide

Renato J. Scialis and José E. Manautou
Journal of Pharmacology and Experimental Therapeutics April 1, 2016, 357 (1) 167-176; DOI: https://doi.org/10.1124/jpet.115.230755
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