5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Comparative Study of Protective Effect of Cimetidine and Verapamil on Paracetamol-Induced Hepatotoxicity in Mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Paracetamol, chemically known as acetaminophen, if taken in higher doses has hepatotoxic potential. Cimetidine by inhibiting the cytochromal enzymes and reducing the production of the toxic metabolite can reduce the hepatotoxic potential while Verapamil can act as a hepatoprotective by maintaining calcium homeostasis. The present study was conducted to study the hepatoprotective activity of Cimetidine and Verapamil against the toxicity induced by paracetamol. In addition to the group receiving only distilled water or 300 mg/kg paracetamol additional groups were added treated with 150 mg/kg Cimetidine and Verapamil alone or both. The Liver function tests and histopathology revealed hepatotoxicity in the group receiving paracetamol (PCM) while normal parameters were observed in the groups receiving Cimetidine and Verapamil. Our results strongly suggested that Cimetidine and Verapamil possess hepatoprotective potential against paracetamol induced hepatotoxicity.

          Related collections

          Most cited references20

          • Record: found
          • Abstract: not found
          • Article: not found

          Mechanism of Action of Paracetamol

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Acetaminophen Relieves Inflammatory Pain through CB1Cannabinoid Receptors in the Rostral Ventromedial Medulla

            Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action. Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB 1 receptors by the acetaminophen metabolite and endocannabinoid reuptake inhibitor AM 404. However, the contribution of the cannabinoid system to antihyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB 1 receptors have remained elusive. Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent antihyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their antihyperalgesic activity in CB 1 −/− mice, confirming the involvement of the cannabinoid system. Consistent with a mechanism downstream of proinflammatory prostaglandin formation, acetaminophen also reversed hyperalgesia induced by intrathecal prostaglandin E 2 . To distinguish between a peripheral/spinal and a supraspinal action, we administered acetaminophen and AM 404 to hoxB8-CB 1 −/− mice, which lack CB 1 receptors from the peripheral nervous system and the spinal cord. These mice exhibited unchanged antihyperalgesia indicating a supraspinal site of action. Accordingly, local injection of the CB 1 receptor antagonist rimonabant into the rostral ventromedial medulla blocked acetaminophen-induced antihyperalgesia, while local rostral ventromedial medulla injection of AM 404 reduced hyperalgesia in wild-type mice but not in CB 1 −/− mice. Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB 1 receptors reside in the rostral ventromedial medulla. SIGNIFICANCE STATEMENT Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action, including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue-specific CB 1 receptor-deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Direct Oxidation and Covalent Binding of Isoniazid to Rodent Liver and Human Hepatic Microsomes: Humans Are More Like Mice than Rats

              Isoniazid (INH) is associated with serious liver injury and autoimmunity. Classic studies in rats indicated that a reactive metabolite of acetylhydrazine is responsible for the covalent binding and toxicity of INH. Studies in rabbits suggested that hydrazine might be the toxic species. However, these models involved acute toxicity with high doses of INH, and INH-induced liver injury in humans has very different features than such animal models. In this study, we demonstrated that a reactive metabolite of INH itself can covalently bind in the liver of mice and also to human liver microsomes. Covalent binding also occurred in rats, but it was much less than that in mice. We were able to trap the reactive metabolite of INH with N-α-acetyl-l-lysine in incubations with human liver microsomes. This suggests that the reactive intermediate of INH that leads to covalent binding is a diazohydroxide rather than a radical or carbocation because those reactive metabolites would be too reactive to trap in this way. Treatment of mice or rats with INH for up to 5 weeks did not produce severe liver injury. The alanine transaminase assay (ALT) is inhibited by INH, and other assays such as glutamate and sorbitol dehydrogenase (SDH) were better biomarkers of INH-induced liver injury. High doses of INH (200 and 400 mg/kg/day) for one week produced steatosis in rats and an increase in SDH, which suggests that it can cause mitochondrial injury. However, steatosis was not observed when INH was given at lower doses for longer periods of time to either mice or rats. We propose that covalent binding of the parent drug can contribute to INH-induced hepatotoxicity and autoimmunity. We also propose that these are immune-mediated reactions, and there are clinical data to support these hypotheses.
                Bookmark

                Author and article information

                Contributors
                Journal
                Int J Hepatol
                Int J Hepatol
                IJH
                International Journal of Hepatology
                Hindawi
                2090-3448
                2090-3456
                2020
                23 January 2020
                : 2020
                : 9185361
                Affiliations
                1Sulaiman Bin Abdullah Aba Al-Khail Centre for Interdisciplinary Research in Basic Sciences (CIRBS), International Islamic University Islamabad (IIUI), Islamabad, Pakistan
                2Department of Maxillofacial Surgery, Rehman College of Dentistry, Peshawar, Pakistan
                3Northwest School of Medicine, Phase-V Hayatabad, Peshawar, Pakistan
                4Department of Medicine, Khyber Teaching Hospital, Peshawar, Pakistan
                5Department of Pharmacology, National Institute of Health (NIH), Islamabad, Pakistan
                Author notes

                Academic Editor: Simon Bramhall

                Author information
                https://orcid.org/0000-0001-8653-1627
                Article
                10.1155/2020/9185361
                6998752
                a2adad7c-575c-48c1-878d-e187ba27b74c
                Copyright © 2020 Lubna Danish et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 October 2019
                : 25 November 2019
                Funding
                Funded by: National Institutes of Health
                Categories
                Research Article

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

                Comments

                Comment on this article