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

Ignazio Grattagliano, Leonilde Bonfrate, Catia V. Diogo, Helen H. Wang, David Q.H. Wang, Piero Portincasa

Research output: Contribution to journalReview article

87 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)4865-4876
Number of pages12
JournalWorld Journal of Gastroenterology
Volume15
Issue number39
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Fingerprint

Chemical and Drug Induced Liver Injury
Mitochondria
Enzyme Induction
Preexisting Condition Coverage
Mitochondrial Membrane Potential
Poisons
Liver
Cholestasis
Xenobiotics
Blister
Cytochrome P-450 Enzyme System
Adenosine Triphosphatases
Liver Diseases
Hepatocytes
Immune System
Permeability
Necrosis
Antioxidants
Adenosine Triphosphate
Genotype

Keywords

  • Adverse effects
  • Apoptosis
  • Drug toxicity
  • Liver diseases
  • Microsomes
  • Mitochondria
  • Necrosis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Grattagliano, I., Bonfrate, L., Diogo, C. V., Wang, H. H., Wang, D. Q. H., & Portincasa, P. (2009). Biochemical mechanisms in drug-induced liver injury: Certainties and doubts. World Journal of Gastroenterology, 15(39), 4865-4876. https://doi.org/10.3748/wjg.15.4865

Biochemical mechanisms in drug-induced liver injury : Certainties and doubts. / Grattagliano, Ignazio; Bonfrate, Leonilde; Diogo, Catia V.; Wang, Helen H.; Wang, David Q.H.; Portincasa, Piero.

In: World Journal of Gastroenterology, Vol. 15, No. 39, 01.12.2009, p. 4865-4876.

Research output: Contribution to journalReview article

Grattagliano, I, Bonfrate, L, Diogo, CV, Wang, HH, Wang, DQH & Portincasa, P 2009, 'Biochemical mechanisms in drug-induced liver injury: Certainties and doubts', World Journal of Gastroenterology, vol. 15, no. 39, pp. 4865-4876. https://doi.org/10.3748/wjg.15.4865
Grattagliano, Ignazio ; Bonfrate, Leonilde ; Diogo, Catia V. ; Wang, Helen H. ; Wang, David Q.H. ; Portincasa, Piero. / Biochemical mechanisms in drug-induced liver injury : Certainties and doubts. In: World Journal of Gastroenterology. 2009 ; Vol. 15, No. 39. pp. 4865-4876.
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