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      Isoniazid metabolism and hepatotoxicity

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          Abstract

          Isoniazid (INH) is highly effective for the management of tuberculosis. However, it can cause liver injury and even liver failure. INH metabolism has been thought to be associated with INH-induced liver injury. This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.

          Graphical abstract

          Isoniazid (INH) is highly effective for the management of tuberculosis. However, it can cause liver injury and even liver failure. INH metabolism has been thought to be associated with INH-induced liver injury. This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.

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          Role of CYP2E1 in the hepatotoxicity of acetaminophen.

          J Ordi Ros, P. Fernandez Martinez, S Lee … (1996)
          CYP2El, a cytochrome P-450 that is well conserved across mammalian species, metabolizes ethanol and many low molecular weight toxins and cancer suspect agents. The cyp2e1 gene was isolated, and a mouse line that lacks expression of CYP2E1 was generated by homologous recombination in embryonic stem cells. Animals deficient in expression of the enzyme were fertile, developed normally, and exhibited no obvious phenotypic abnormalities, thus indicating that CYP2E1 has no critical role in mammalian development and physiology in the absence of external stimuli. When cyp2el knockout mice were challenged with the common analgesic acetaminophen, they were found to be considerably less sensitive to its hepatotoxic effects than wild-type animals, indicating that this P-450 is the principal enzyme responsible for the metabolic conversion of the drug to its active hepatotoxic metabolite.
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            Oxidative stress, toxicology, and pharmacology of CYP2E1.

            A Caro, Arthur I. Cederbaum (2003)
            This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
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              Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis.

              Johannes W Jacobs, D A Rozwarski, James C. Sacchettini … (1998)
              The preferred antitubercular drug isoniazid specifically targets a long-chain enoyl-acyl carrier protein reductase (InhA), an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Despite the widespread use of this drug for more than 40 years, its precise mode of action has remained obscure. Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the nicotinamide ring of nicotinamide adenine dinucleotide bound within the active site of InhA.
              Article 0 comments Cited 89 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaochao Ma
                Journal
                Journal ID (nlm-ta): Acta Pharm Sin B
                Journal ID (iso-abbrev): Acta Pharm Sin B
                Title: Acta Pharmaceutica Sinica. B
                Publisher: Elsevier
                ISSN (Print): 2211-3835
                ISSN (Electronic): 2211-3843
                Publication date PMC-release: 03 August 2016
                Publication date (Print): September 2016
                Publication date (Electronic): 03 August 2016
                Volume: 6
                Issue: 5
                Pages: 384-392
                Affiliations
                [a ]Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
                [b ]Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA
                Author notes
                [* ]Corresponding author. Tel.: +1 412 648 9448. mxiaocha@ 123456pitt.edu
                Article
                Publisher ID: S2211-3835(16)30127-7
                DOI: 10.1016/j.apsb.2016.07.014
                PMC ID: 5045547
                PubMed ID: 27709007
                SO-VID: f81c641e-aeb1-4156-a026-9630b09c91f7
                Copyright © © 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 15 April 2016
                Date revision received : 9 June 2016
                Date accepted : 27 June 2016
                Categories
                Subject: Review

                Keywords: achz, acetylhydrazine,acinh, acetylisoniazid,alp, alkaline phosphatase,alt, alanine aminotransferase,diachz, diacetylhydrazine,gsh, glutathione,gst, glutathione s-transferase,hz, hydrazine,ina, isonicotinic acid,inh, isoniazid,mpo, myeloperoxidase,nad+, nicotinamide adenine dinucleotide,nat, n-acetyltransferase,p450, cytochrome p450,r.m., reactive metabolite,tb, tuberculosis,isoniazid,metabolism,hepatotoxicity,anti-tuberculosis,n-acetyltransferase 2,amidase
                Data availability:
                Keywords: achz, acetylhydrazine, acinh, acetylisoniazid, alp, alkaline phosphatase, alt, alanine aminotransferase, diachz, diacetylhydrazine, gsh, glutathione, gst, glutathione s-transferase, hz, hydrazine, ina, isonicotinic acid, inh, isoniazid, mpo, myeloperoxidase, nad+, nicotinamide adenine dinucleotide, nat, n-acetyltransferase, p450, cytochrome p450, r.m., reactive metabolite, tb, tuberculosis, isoniazid, metabolism, hepatotoxicity, anti-tuberculosis, n-acetyltransferase 2, amidase

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