TITLE

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

AUTHOR(S)
Grattagliano, Ignazio; Bonfrate, Leonilde; Diogo, Catia V.; Wang, Helen H.; Wang, David Q. H.; Portincasa, Piero; Shimizu, Yukihiro
PUB. DATE
October 2009
SOURCE
World Journal of Gastroenterology;10/21/2009, Vol. 15 Issue 39, p4865
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca2+-dependent ATPase, reduced capability to sequester Ca2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
ACCESSION #
44861316

 

Related Articles

  • Immune cell-mediated liver injury. Corazza, Nadia; Badmann, Anastasia; Lauer, Christoph // Seminars in Immunopathology;Jul2009, Vol. 31 Issue 2, p267 

    Liver diseases represent an important cause of morbidity and mortality in the world. Death of hepatocytes and other hepatic cell types is a characteristic feature of several forms of liver injury such as cholestasis, viral hepatitis, drug- or toxin-induced injury, and alcohol-induced liver...

  • Cholestatic Liver Disease with Ductopenia (Vanishing Bile Duct Syndrome) After Administration of Clindamycin and Trimethoprim-Sulfamethoxazole. Altraif, Ibrahim; Lilly, Leslie; Wanless, Ian R.; Heathcote, Jenny // American Journal of Gastroenterology;Aug1994, Vol. 89 Issue 8, p1230 

    Two patients who developed cholestatic liver disease after exposure to antibiotics are described. One patient who received clindamycin had liver biopsy findings of marked cholestasis, portal inflammation, bile duct injury and bile duct paucity (ductopenia). A second biopsy after clinical...

  • Kavain.  // Reactions Weekly;12/13/2008, Issue 1232, p23 

    The article describes several cases of liver injury induced by kavain/kavapyrone therapy. Six women and two men aged 26-60 years developed hepatotoxicity such as necrosis, hepatitis, intrahepatic cholestasis, cholangitis and hepatic eosinophilia. It relates the kavapyrone dosages received by the...

  • Hepatic Drug-Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment. MOHUTSKY, MICHAEL A.; ROMEIKE, ANNETTE; MEADOR, VINCE; LEE, WILLIAM M.; FOWLER, JOHN; FRANCKE-CARROLL, SABINE // Toxicologic Pathology;Aug2010, Vol. 38 Issue 5, p799 

    Hepatic drug metabolizing enzyme (DME) induction complicates the development of new drugs owing to altered efficacy of concomitant treatments, reduction in exposure resulting from autoinduction, and potential generation of toxic metabolites. Risk assessment of DME induction during clinical...

  • Methylprednisolone.  // Reactions Weekly;6/23/2007, Issue 1157, p19 

    The article describes the medical case of a 34-year-old man who developed liver cell necrosis during treatment with methylprednisolone for multiple sclerosis. The patient initially received methylprednisolone 1g intravenously (IV) daily for five days, followed by maintenance therapy of IV...

  • Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis. Renga, Barbara; Mencarelli, Andrea; D'Amore, Claudio; Cipriani, Sabrina; D'Auria, Maria Valeria; Sepe, Valentina; Chini, Maria Giovanna; Monti, Maria Chiara; Bifulco, Giuseppe; Zampella, Angela; Fiorucci, Stefano // PLoS ONE;Jan2012, Vol. 7 Issue 1, p1 

    Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly...

  • Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis. Renga, Barbara; Mencarelli, Andrea; D'Amore, Claudio; Cipriani, Sabrina; D'Auria, Maria Valeria; Sepe, Valentina; Chini, Maria Giovanna; Monti, Maria Chiara; Bifulco, Giuseppe; Zampella, Angela; Fiorucci, Stefano // PLoS ONE;Jan2012, Vol. 7 Issue 1, p1 

    Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly...

  • Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease. Mitchell, Claudia; Mahrouf-Yorgov, Meriem; Mayeuf, Alicia; Robin, Marie-Anne; Mansouri, Abdellah; Fromenty, Bernard; Gilgenkrantz, Hélène // Laboratory Investigation (00236837);Feb2011, Vol. 91 Issue 2, p273 

    The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis,...

  • Allopurinol.  // Reactions Weekly;6/26/2004, Issue 1007, p7 

    Presents a case study of a woman who developed hepatic centrilobular haemorrhagic necrosis associated with allopurinol hypersensitivity syndrome during treatment with allopurinol. Health history of the woman; Side effects experienced by the woman after receiving the drug; Result of the...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics