The document summarizes various biochemical mechanisms that can cause drug-induced liver injury (DILI), including reactions with the cytochrome P450 system and formation of reactive metabolites that damage cellular structures. It also discusses how DILI can trigger both adaptive and innate immune responses through mechanisms like the hapten hypothesis or direct stimulation of T cells. Underlying inflammation from factors like infection may exacerbate DILI by augmenting the toxic response through innate immune system activation.

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

2. Biochemical mechanisms of liver injury

3. P450 system
The primary metabolic pathway for
the majority of drugs entails the
cytochrome P450 (CYP450) system.
P450 system is a supergene family of
heme-containing, mixed-function
oxidase enzymes.

5. 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.

6. Reactive metabolites
• The disruption of subcellular actin
filaments and interruption of transport
pumps at the canalicular membrane
may generate abnormal bile flow:
prevention of the bilirubin excretion.
• Final result is cholestasis and jaundice.

7. Free radical intermediates
Certain drugs may induce mitochondrial
dysfunction through inhibition of fatty acid
oxidation and energy production resulting in a
decrease in ATP production.
Inhibition of mitochondrial function and lack of
aerobic respiration may further generate free
radical intermediates.
Free radical intermediates can directly damage cell
membranes via lipid peroxidation, target
nucleophilic DNA residues or increase oxidative
stress.

8. Immune reactions and liver injury

9. Immune reactions
Hepatic cellular
dysfunction and
death have the
ability to initiate
immunological
reactions, including
both adaptive and
innate immune
responses.

10. Adaptive immune response
• Drug induced liver injury (DILI) cases caused by
adaptive immune response usually occur within
1-4 weeks after initial drug treatment.
• These cases are often accompanied by
symptoms of an allergic drug reaction (skin
rash, fever) and biopsy specimens revealing
evidence of monocytic or eosinophilic
infiltration.
Gunawan and Kaplowitz 2004

11. Adaptive immune response
• These reactions tend to occur only upon
reexposure and the presence of antibodies
directed against native or drug-modified
hepatic proteins.
• Drugs such as halothane, tienilic acid,
dihydralazine, diclofenac and carbamazepine
have been implicated in the initiation of
adaptive immunity.
Zimmerman 1999

12. Hapten hypothesis
• Drugs, or more often their reactive
metabolites, act as haptens and irreversibly
bind to and modify proteins to form drug-
protein adducts (neoantigens).
• Neoantigens are perceived as foreign by
the immune system and induce a hapten-
specific immune response.
Park et al. 1998
Uetrecht 1999

13. p-i concept
Drugs are directly able to stimulate
T cells via interaction with the T cell
receptor without the requirement
for metabolism or hapten-protein
formation and antigen presentation
by antigen presenting cells (APCs).
Pichler 2002, 2005

14. Innate immune response
Cellular mediators of innate immunity include
tissue macrophages, polymorphonuclear
leukocytes (neutrophils, eosinophils and
basophils), natural killer (NK) cells and NK cells
with T cell receptors (NKT cells).
Functions are recognition of microbial molecular
patterns and generation of antimicrobial
peptides, cytokine elaboration, activation of
complement and mediation of opsonization,
phagocytosis of infected cells and microbes,
direct killing of virus-infected cells.
Janeway and Medzhitov 2002

15. Innate immune response
• Hepatic innate immune cells play a key role
in the progression and severity of tissue
injury in some cases of DILI.
• Damaged hepatocytes release damage-
associated molecular pattern (DAMP)
molecules, which induce a proinflammatory
activation of innate immune cells, thereby
contributing to the pathogenesis of DILI.

16. Underlying inflammation
A variety of cellular stresses may exacerbate DILI:
• direct cellular injury by a drug or metabolite
• temperature stress
• oxidative stress
• activation of cell death-inducing pathways
• viral or bacterial infection
Ganey and Roth 2001
Park et al. 2000

17. Underlying inflammation
Episodes of inflammation,
such as bacterial or viral
infection concurrent with
drug treatment, may
augment the toxic response.

18. Underlying inflammation
Concurrent infection,
through the activation
of the hepatic innate
immune system and
subsequent
inflammation,
increases a patient’s
risk of developing DILI.

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