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Drug-induced liver injury part II

Drug-induced liver injury part II. Domina Petric, MD. Biochemical m echanism s of l iver i njury. P450 system. Reactive metabolites.

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Drug-induced liver injury part II

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  1. Drug-induced liver injury part II Domina Petric, MD

  2. Biochemical mechanismsof liverinjury

  3. P450 system

  4. Reactive metabolites • The covalent adduction of reactive metabolites to critical cellular macromolecules may disrupt and inhibit calcium gradients and ionic homeostasis leading to a decline in ATP levels. • This process may also disrupt the endoplasmic reticulum, microtubules and cytoskeleton, resulting in cell swelling or lysis.

  5. Reactive metabolites • The disruption of subcellular actinfilaments and interruption of transport pumps at the canalicular membrane maygenerateabnormal bile flow: prevention of the bilirubin excretion. • Final result is cholestasis and jaundice.

  6. Free radical intermediates

  7. Immune reactionsandliver injury

  8. Immune reactions

  9. Adaptive immune response • Drug induced liver injury (DILI) cases caused by adaptive immune responseusually occur within 1-4 weeksafter initial drug treatment. • These cases are often accompanied by symptoms of an allergicdrug reaction(skin rash, fever)and biopsy specimens revealing evidence ofmonocyticor eosinophilic infiltration. Gunawan and Kaplowitz 2004

  10. Adaptive immune response • Thesereactions tend to occur only upon reexposure and the presence of antibodiesdirected against native or drug-modified hepatic proteins. • Drugs such as halothane, tienilicacid,dihydralazine, diclofenac and carbamazepine have been implicated in the initiation of adaptive immunity. Zimmerman1999

  11. Haptenhypothesis • Drugs, or more often their reactive metabolites, act ashaptensand irreversibly bind to and modify proteins to form drug-protein adducts(neoantigens). • Neoantigensare perceived as foreign by the immune system and induce ahapten-specific immune response. Park et al. 1998Uetrecht 1999

  12. p-iconcept Pichler 2002, 2005

  13. Innate immune response Janeway and Medzhitov 2002

  14. Innate immune response • Hepaticinnate immune cells play a key role in the progressionand severity of tissue injury in some cases of DILI. • Damagedhepatocytes release damage-associated molecular pattern (DAMP)molecules, which induce aproinflammatoryactivation of innate immune cells,thereby contributing to the pathogenesis of DILI.

  15. Underlying inflammation A variety of cellular stresses may exacerbate DILI: • direct cellularinjury by a drug or metabolite • temperature stress • oxidative stress • activation of celldeath-inducing pathways • viral or bacterial infection Ganey and Roth2001 Park et al. 2000

  16. Underlying inflammation

  17. Underlying inflammation

  18. Literature • Holt M. Ju C. Drug-Induced Liver Injury. In: Uetrecht. J. Adverse Drug Reactions. Springer;2010.p.3-29.

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