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      Tramadol-induced hepato- and nephrotoxicity in rats: Role of Curcumin and Gallic acid as antioxidants

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          Abstract

          Tramadol is an analgesic used to treat moderate to severe pain caused by cancer, osteoarthritis, and other musculoskeletal diseases. Cytochrome P450 system metabolizes tramadol and induces oxidative stress in different organs. Therefore, the present study aims at investigating the changes in the activities and the protein expressions of CYPs isozymes (2E1, 3A4, 2B1/2), antioxidants status, free radicals levels after pretreatment of rats with Curcumin and/or Gallic as single- and/or repeated-doses before administration of tramadol. In repeated-dose treatments of rats with tramadol, the activities of cytochrome P450, cytochrome b 5, and NADPH-cytochrome-c-reductase, and the antioxidant enzymes including glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, superoxide dismutase, and levels of glutathione were inhibited in the liver and the kidney of rats. Interestingly, such changes caused by tramadol restored to their normal levels after pretreatment of rats with either Curcumin and/or Gallic acid. On the other hand, repeated-dose treatment of rats with tramadol increased the activities of both dimethylnitrosamine N-demethylase I (DMN-dI), and aryl hydrocarbon hydroxylase (AHH) compared to the control group. However, pretreatment of rats with Curcumin and/or Gallic acid prior to administration of tramadol restored the inhibited DMN-dI activity and its protein expression (CYP 2E1) to their normal levels. On the other hand, tramadol inhibited the activity of ethoxycoumarin O-deethylase (ECOD) and suppressed its protein marker expression (CYP2B1/2), whereas Curcumin, Gallic acid and/or their mixture restored such changes to their normal levels. In conclusion, Curcumin and/or Gallic acid alleviated the adverse effects caused by tramadol. In addition, patients should be advice to take Curcumin and/or Gallic acid prior to tramadol treatment to alleviate the hepatic and renal toxicities caused by tramadol.

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          Most cited references63

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          A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase.

          R. F. Beers, I. Sizer (1952)
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            Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism.

            Paul Davis, J Gillette, Charles W. Potter … (1973)
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              Clinical pharmacology of tramadol.

              Armin Sablotzki, Stefan Grond (2003)
              Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.
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                Author and article information

                Contributors
                Salah A. Sheweita:
                ORCID: http://orcid.org/0000-0001-8113-4403
                Role: ConceptualizationRole: Formal analysisRole: SupervisionRole: Writing – review & editing
                Ainour A. Almasmari: Role: InvestigationRole: Methodology
                Sabah G. El-Banna: Role: Formal analysisRole: SupervisionRole: ValidationRole: Writing – original draft
                Ferenc Gallyas Jr.: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 August 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 8
                Electronic Location Identifier: e0202110
                Affiliations
                [1 ] Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandra, Egypt
                [2 ] Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandra, Egypt
                University of PECS Medical School, HUNGARY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-8113-4403
                Article
                Publisher ID: PONE-D-18-03735
                DOI: 10.1371/journal.pone.0202110
                PMC ID: 6093657
                PubMed ID: 30110401
                SO-VID: c88281c3-7e8c-4827-8c10-b6b388102770
                Copyright © © 2018 Sheweita et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 3 February 2018
                Date accepted : 27 July 2018
                Page count
                Figures: 3, Tables: 5, Pages: 18
                Funding
                The author(s) received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Antioxidants
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Renal System
                Subject: Kidneys
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Renal System
                Subject: Kidneys
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Molecular Biology Assays and Analysis Techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Molecular Biology Assays and Analysis Techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Peptides
                Subject: Glutathione
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Enzymology
                Subject: Enzymes
                Subject: Catalases
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Enzymes
                Subject: Catalases
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Enzymology
                Subject: Enzymes
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Enzymes
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Oxidative Stress
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Pharmacokinetics
                Subject: Drug Metabolism
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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