Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Oct 21, 2009; 15(39): 4865-4876
Published online Oct 21, 2009. doi: 10.3748/wjg.15.4865
Biochemical mechanisms in drug-induced liver injury: Certainties and doubts
Ignazio Grattagliano, Leonilde Bonfrate, Catia V Diogo, Helen H Wang, David QH Wang, Piero Portincasa
Ignazio Grattagliano, Leonilde Bonfrate, Piero Portincasa, Clinica Medica “A. Murri”, Dipartimento di Medicina Interna e Medicina Pubblica, University of Bari Medical School, Policlinico, 70124 Bari, Italy
Catia V Diogo, Department of Zoology, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
Helen H Wang, David QH Wang, Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, 330 Brookline Avenue, DA 601, Boston, MA 02215, United States
Author contributions: All authors contributed equally to writing and revising the paper.
Correspondence to: Piero Portincasa, MD, PhD, Clinica Medica “A. Murri”, Dipartimento di Medicina Interna e Medicina Pubblica, University of Bari Medical School, Policlinico, 70124 Bari, Italy. p.portincasa@semeiotica.uniba.it
Telephone: +39-80-5478227 Fax: +39-80-5478232
Received: July 28, 2009
Revised: September 4, 2009
Accepted: September 11, 2009
Published online: October 21, 2009

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.

Keywords: Adverse effects, Apoptosis, Drug toxicity, Liver diseases, Microsomes, Mitochondria, Necrosis