Drug- and Toxin-Induced Damage
Xenobiotics can cause hepatocellular injuries by several different
mechanisms, including (1) covalently binding to and inactivating key enzymes, (2)
peroxidation of membrane lipids, (3) depletion of intracellular antioxidants, and
(4) induction of immunopathologic responses. Certain substances are toxic enough
to damage organelles
(e.g., plasma membrane, mitochondria), interrupt energy production, disrupt ion gradients,
and destroy the physical integrity of the cell. However, the hepatotoxic effects
of most clinically or environmentally relevant compounds occur because of CYP, and
involve reactive metabolites such as carbon-based radicals, nitro-radicals, and reduced
oxygen species. For example, CYP oxidizes carbon tetrachloride to a toxic intermediate,
trichloromethyl radical, which causes centrilobular necrosis. Similarly, hepatic
damage from nitrofurantoin and other aromatic molecules involves free radical intermediates
formed during their metabolism.
Similar to CYP of the smooth endoplasmic reticulum, enzymes of
the mitochondrial electron transport pathway involved in xenobiotic metabolism may
produce reactive intermediates. For example, cocaine or nitrofurantoin metabolism
yields nitro-radicals,[147]
[233]
which can transfer an electron to molecular oxygen via flavoprotein reductases, forming
superoxide and other reactive oxygen species. Reactive intermediates can arise by
many other mechanisms, including redox cycling reactions, as occurs with anthracycline
chemotherapeutics or imidazole antimicrobial agents.
Various drugs can damage the liver by weakening antioxidant defense
mechanisms. Examples include acetaminophen and bromobenzene, which cause extensive
liver necrosis by draining hepatocellular stores of reduced glutathione.[281]
[282]
Further oxidative stresses can damage important
proteins and enzymes, phospholipids in membranes, and nucleotides by activating proteases,
phospholipases, and endonucleases. Oxidative stress causes pathologic increases
in cytosolic Ca2+
by allowing excessive uptake of Ca2+
into
cells and stimulating Ca2+
release from intracellular storage pools (from
the endoplasmic reticulum or mitochondria). These events can induce apoptosis, necrosis,
or both.
Occasionally, conjugation pathways produce reactive intermediates,
such as acyl glucuronides (metabolites of carboxylate drugs), which can damage the
liver.[153]
[283]
[284]
[285]
Injury
typically occurs when intermediates covalently bind to and inactivate essential molecules—particularly
nucleophiles, thiol-rich proteins, and nucleic acids. Intermediates can also damage
the liver through depletion of antioxidant stores (oxidative stress) or by inducing
neoantigens and autoantigen formation, which subsequently trigger immunopathologic
responses.
Drug-Induced Apoptosis
Drugs that induce oxidative stress and mitochondrial injury can
trigger intracellular apoptotic pathways.[233]
[236]
[243]
The following events may be involved: (1)
CYP produces reactive drug metabolites; (2) these metabolites deplete glutathione;
(3) mitochondria are injured, with cytochrome c release and operation of the mitochondrial
membrane permeability transition; (4) capsaicin is activated; and (5) apoptosis occurs.
[236]
[286]
[287]
[288]
Enzymes in mitochondria are likely to be
a
pathogenically important target of the acetaminophen metabolite N-acetyl-p-benzoquinone
imine (NAPQI). The characteristic hepatic pathology of Reye's syndrome may reflect
mitochondrial injury induced by drugs such as tetracycline, aspirin, valproic acid,
and certain nucleoside analogs (e.g., zidovudine).[288]
Whether mitochondrial injury causes apoptosis or necrosis depends on the energy
state of the cell as well as on the acuteness and severity of the injury.[233]
When ATP levels decline slowly, apoptosis may occur, whereas rapid energy depletion
causes necrosis.
Immunopathology
Immunopathology often underlies idiosyncratic adverse drug reactions
that affect the liver. Halothane hepatitis provides a prototypic example. The clinical
features of such reactions characteristically include (1) a delayed onset after the
first drug exposure and a hastened onset following later challenges; (2) fever, rash,
or lymphadenopathy; and (3) eosinophilia and inflammatory infiltrates in the liver.
Immunopathologic events may involve (1) production of antibodies that lyse hepatocytes
via molecular mimicry with host enzymes[289]
; (2)
antibody-dependent cell-mediated immunity, such as occurs with diclofenac[290]
;
and (3) dysregulation of the immune system or drug-induced autoimmunity.[291]
[292]
According to the altered antigen concept, drug metabolites alter
cellular proteins, causing drug-protein adducts or neoantigens to form. For example,
trifluoroacylated (TFA) adducts form after exposure to halothane or other halogenated
anesthetics.[293]
Antibodies directed against TFA
protein adducts are often present in patients recovering from halothane-induced liver
injury. However, the specificity and pathogenicity of these antibodies remain unclear,
[293]
because only a tiny fraction of the patients
that make these antibodies suffer hepatic injury. Tissue-damaging immune responses
seem to require a chain of events. For example, Kupffer cells, in association with
mixed histocompatibility complex (MHC), process the adduct molecules. Responsive
CD4+
T cells induce the immune response, and the target cells express
drug-derived antigen and a class II MHC molecule, which attracts CD8+
(cytotoxic) T cells. The development of autoimmune disease may involve genetic predisposition
through anomalies of immune tolerance. Dysregulation of the immune system induces
autoantibodies to form. Some autoantibodies are organ-specific, like the liver-kidney
microsomal (LKM) antibodies that target microsomal enzymes (after halothane hepatitis,
LKM antibodies are directed at CYP2El), whereas others lack tissue specificity, such
as antinuclear and smooth muscle antibodies.
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