TY - JOUR
T1 - Biochemical mechanisms in drug-induced liver injury
T2 - Certainties and doubts
AU - Grattagliano, Ignazio
AU - Bonfrate, Leonilde
AU - Diogo, Catia V.
AU - Wang, Helen H.
AU - Wang, David Q.H.
AU - Portincasa, Piero
PY - 2009
Y1 - 2009
N2 - 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 Ca 2+-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.
AB - 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 Ca 2+-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.
KW - Adverse effects
KW - Apoptosis
KW - Drug toxicity
KW - Liver diseases
KW - Microsomes
KW - Mitochondria
KW - Necrosis
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U2 - 10.3748/wjg.15.4865
DO - 10.3748/wjg.15.4865
M3 - Review article
C2 - 19842215
AN - SCOPUS:73949098595
SN - 1007-9327
VL - 15
SP - 4865
EP - 4876
JO - World Journal of Gastroenterology
JF - World Journal of Gastroenterology
IS - 39
ER -