The general mechanism by which most drugs induce liver injury is based on the unusual susceptibility of individual patients.
MECHANISMS OF DRUG-INDUCED LIVER
INJURY
The
general mechanism by which most drugs induce liver injury is based on the
unusual susceptibility of individual patients. For some drugs, the
idiosyncratic reaction is immunologically mediated and for others metabolic
idiosyncrasy may be responsible. Even though such classification of
drug-induced liver injury is simplistic and the molecular basis of the
idiosyn-cratic drug-induced liver injury is poorly understood, some key events
have emerged as being particularly important.
The
suggestion of dose dependence in some cases of drug-induced liver injury
indicates that a host-dependent idiosyncrasy in the metabolism or excretion of
these drugs may be responsible for hepa-totoxicity. Although several
xenobiotics are trans-formed by the cytochrome P450 system (CYPs) into stable
metabolites, many others are oxidised into unstable, chemically reactive
intermediates. These reactive intermediates attack hepatic constituents such as
unsaturated lipids, proteins or DNA and can lead to liver cell death (Pessayre,
1995). The abun-dance of CYPs in the liver explains the major role of these
metabolites in drug-induced hepatotoxic-ity. Furthermore, the centrilobular
location of most CYPs accounts for the pericentral location of these lesions.
When small amounts of reactive metabolites are formed, glutathione serves as a
decoy target, spar-ing critical hepatic macromolecules. However, when large
amounts of the reactive metabolite are formed, the formation of glutathione
conjugates exceeds the capacity of the liver to synthesise glutathione. The
resulting depletion of glutathione together with direct covalent binding of the
metabolite protein thiols has serious consequences. The oxidation of protein
thiol groups results in the formation of disulphur bonds between different
molecules of actin, result-ing in destruction of the microfilamentous network
beneath the plasma membrane (Mirabelli et
al., 1988). The depletion of protein thiol groups also decreases the
activity of calcium translocases resulting in increases in intracellular Ca2+ that further
damages the cytoskeleton (Bellomo and Orrenius, 1985). These and other effects
of oxidative stress lead to the swelling and disruption on intracellular
organelles ultimately resulting in hepatocyte necrosis.
Although
it was initially thought that the toxic-ity of reactive metabolites only caused
cell necro-sis, this idea has been challenged in recent years (Pessayre et al., 1999). It is now clear that the
exten-sive formation of reactive metabolites can cause apop-tosis, necrosis or
both (Fau et al., 1997; Shi et al., 1998). Several compounds, such
as acetaminophen and cocaine, transformed into reactive metabolites have been
shown to cause DNA fragmentation of hepatocytes indicative of apoptosis (Shen et al., 1992; Cascales et al., 1994). The cellular mechanisms
caus-ing metabolite-induced apoptosis have been studied with germander, a
medicinal plant used in weight control diets, the widespread use of which led
to an epidemic of hepatitis in France (Larrey et al., 1992b). Germander contains furano diterpenoids, which are
activated by CYP 3A into electrophilic metabo-lites (Lekehal et al., 1996). Extensive formation of glutathione
depletion, which in combination with covalent binding of the metabolites,
results in protein thiol oxidation (Lekehal et
al., 1996). The oxida-tion of protein thiols inactivates plasma membrane
calcium translocases and increases the permeability of the mitochondrial inner
membrane (the mitochon-drial membrane permeability transit or MMPT), which
through the release of cytochrome C leads to the acti-vation of caspases
(Fagian et al., 1990). Caspases are
cysteine proteases that cut proteins after an aspartate residue and are the
major executioners of apopto-sis (Thornberry and Lazebnik, 1998). Caspase
acti-vation in conjunction with increased intra-cellular calcium activates
calcium-dependent endonucleases, which cut the DNA between nucleosomes, eventually
resulting in apoptosis (Fau et al.,
1997). Germander-induced apoptotic hepatocyte death is prevented by
troleandomycin, which inhibits its metabolic activa-tion by CYP 3A4 or by
preventing the depletion of glutathione with cysteine (Fau et al., 1997).
Hepatotoxicity
from the reactive metabolites of drugs is a significant problem with drugs
where the forma-tion of reactive metabolites is low enough to ensure the
absence of hepatotoxicity in most recipients (and therefore allowing the
marketing of the drug) but is high enough to lead to ‘idiosyncratic’ toxicity
in some ‘susceptible’ subjects. The reason for susceptibility could be either
genetically determined or acquired.
The
amount of reactive metabolite formed depends on a particular isoenzyme the
hepatic level of which may vary between individuals. Genetic polymorphisms of
drug-metabolising enzymes may contribute to an indi-vidual’s risk to an ADR.
Polymorphism in debriso-quine oxidation (CYP 2D6) leads to the accumula-tion of
perhexiline resulting in liver injury in poor metabolisers (Morgan et al., 1984) and increases the
formation of reactive metabolites leading to chlor-promazine hepatotoxicity in
extensive metabolisers (Watson et al.,
1988). Polymorphism in mepheny-toin hydroxylation (CYP 2C19) may predispose
poor metabolisers to atrium (phenobarbital, febar-bamate and
difebarbamate)-induced hepatotoxicity (Horsmans et al., 1984). Recent studies have shown susceptibility to
isoniazid-induced hepatotoxicity was increased with the possession of both NAT2
geno-type associated with slow acetylation and CYP 2E1 genotype leading to
increased activity (Huang et al.,
2002, 2003).
Individual
susceptibility to hepatotoxicity due to reac-tive metabolites may also be
related to physiologi-cal, nutritional or therapeutic modifications in drug
metabolism. For example, fasting leads to glycogen depletion and decreased
glucuronidation, the deple-tion of glutathione and the induction of CYP 2E1
leading to an increased risk of paracetamol-induced liver injury (Price, Miller
and Jollow, 1987; Whit-comb and Block, 1994). Acquired factors enhancing the
rate of biotransformation of a drug to its reactive metabolites through the
induction of CYP P450 isoen-zymes play an important role in increasing the
direct toxicity. Alcohol is a potent inducer of CYP 2E1 and to a lesser extent
CYP 3A4. Subjects who consume alcohol regularly may therefore have increased
the bioactivation of paracetamol (which is metabolised by CYP 2E1 and CYP 3A4),
resulting in hepato-toxicity at conventional ‘therapeutic’ doses (Zimmer-man
and Maddrey, 1995). In individuals with heavy alcohol intake, this is
compounded by the reduced glutathione synthesis and low glutathione stores due
to the inhibition of glutathione synthetase and ethanol-related oxidative
stress, respectively. Isoniazid also increases the toxicity of paracetamol by
inducing CYP 2E1, whereas rifampicin, another microsomal enzyme inducer, increases
the risk of hepatotoxic-ity due to isoniazid (Moulding, Redeker and Kanel,
1991; Pessayre et al., 1977).
Anticonvulsants (pheny-toin, carbamazepine and phenobarbital) induce CYP 3A4
and can also enhance the toxic effects of parac-etamol (Bray et al., 1992). As an alternative
mech-anism of drug interaction leading to an increased risk of
paracetamol-induced liver injury, zidovudine competes for glucuronidation of
the toxic metabo-lite, thus reducing its excretion (Shriner and Goetz, 1992).
Drug accumulation can result from metabolic inhibition caused by another drug.
For instance, trole-andomycin increases the risk of cholestasis with oral
contraceptives by inhibiting the CYP 3A responsible for oestrogen oxidation
(Miguet et al., 1980).
The
presence of underlying liver disease may predispose to dose-dependent drug
toxicity, especially if the margin between therapeutic and toxic
concen-trations is small (Schenker, Martin and Hoyumpa, 1999). It is generally
believed that pre-existing liver disease would neither induce nor worsen the
idiosyn-cratic hepatotoxicity, although this issue has not been studied
adequately. However, a recent study demon-strated a higher incidence of
hepatotoxicity as well as more severe liver injury secondary to
antituberculo-sis agents in hepatitis B virus (HBV) carriers when compared with
non-carriers and with HBV carriers who did not receive antituberculosis therapy
(Wong et al., 2000).
The
clinico-pathologic features of some idiosyncratic drug reactions suggest that
immunological mecha-nisms could play an important role in the patho-genesis of
drug hepatotoxicity. These include (a) a fever, rash, lymphadenopathy,
eosinophilia and involvement of other organs; (b) hepatic inflamma-tory
infiltrates; (c) low frequency (<1/1000 users); (d) delay in appearance of
the disease (2 weeks to several months); and (e) accelerated onset after
rechal-lenge (Beaune and Lecoeur, 1997; Robin et al., 1997). In hepatitis, secondary to sulphonamides, phenytoin
and nitrofurantoin, the liver is implicated as part of a systemic
hypersensitivity reaction, and evidence for immunological responsiveness to
these drugs can be obtained by in vitro
rechallenge with the drug or its metabolite (Spielberg et al., 1981; Shear and Spielberg, 1988; Rieder et al., 1989). Interestingly, the immune
response may not be directed at the drug per
se but at compounds arising because of its metabolism. Drug hepatotoxicity
may therefore be the result of both metabolic and immunological idiosyncrasy.
In this respect, the superimposition of CYP P450 and the immune system in the
liver have potential disadvantages. The covalent binding of the reactive
metabolites to ‘self’ proteins results in the formation of neo-antigens that
‘mislead’ the immune system into mounting an immune response against
hepatocytes.
The
initial and crucial event underlying the so-called ‘immuno-allergic hepatitis’
is the oxida-tive metabolism of a drug by a CYP P450 enzyme resulting in the
formation of reactive metabolites. Electrophilic metabolites react with and
covalently bind to nucleophilic groups of patients to form protein adducts. The
best-studied example is that of halothane, which is oxidised into a reactive
acyl chlo-ride (CF3COC1) by CYP P450 2E1. The metabolite reacts with
the -NH2 group of the lysine residues of proteins to form
trifluoroacetylated proteins (CF3CO-lysine proteins) (Gut, Christen
and Huwyler, 1993). The reactive metabolite may also bind covalently to the CYP
2E1 protein itself (Eliasson and Kenna, 1996). The alkylation of CYP P450
proteins may lead both to anti-P450 autoantibodies and to antibodies against
the modified part of the protein. Therefore, a single drug such as halothane
may concomitantly give rise to both ‘immune-allergic’ and ‘autoimmune’ hepatitis.
Genetic
factors influencing the development of the immune-mediated drug hepatotoxicity
can be grouped into factors affecting the amount of the reactive metabolite and
therefore protein adduct formed and factors affecting the immune response to
these adducts (Aithal, 2004). Dihydralazine hepatitis is a good example of how
a ‘metabolic’ genetic factor can contribute to susceptibility to
immune-mediated hepa-totoxicity. Dihydralazine is predominantly acetylated by
the polymorphic N -acetyl transferase 2. In slow acetylators, the majority of
the drug is available for metabolic activation by CYP 1A2 into a free radi-cal.
Hence, the alkylation of hepatic proteins is more extensive, and the incidence
of immune-mediated hepatitis is higher (Bourdi et al., 1994).
The
second group of genetic factors influencing susceptibility to immune-mediated
hepatic drug reac-tions is the genes whose products are involved in immune
regulation. Genetic polymorphism in major histocompatibility complex (MHC)
molecules is the most obvious example. The presence or absence of a given human
leukocyte antigen (HLA) molecule may determine the efficient presentation of an
alky-lated immunogenic peptide. Associations have been reported between HLA A11
and hepatotoxicity due to halothane, tricyclic antidepressants and diclofenac,
HLA DR6 and liver injury secondary to chlorpro-mazine and nitrofurantoin, HLA
B8 and clometacine hepatitis (Berson et
al., 1994). Two case–control stud-ies involving Caucasian population have
demon-strated that co-amoxiclav-induced jaundice is strongly associated with
HLA DRB1*1501-DRB5*0101-DQB1*0602 haplotype (Hautekeete et al., 1999, O’Donohue et al.,
2000). Subjects carrying the extended haplotype would be at nine times higher
risk of developing ADR to co-amoxiclav (O’Donohue et al., 2000). More recently, genetic polymorphism in gene-encoding immunomodulatory
cytokines such as interleukin-10 (IL-10) and IL-4 has been shown to influence
the risk of diclofenac-induced hepatotoxic-ity (Aithal, 2004).
Cholestasis
From
experimental models, several mechanisms have been postulated for impaired bile
secretion. They are the inhibition of Na+, K+ATPase resulting in reduced uptake
of bile acids, increased pericellular permeabil-ity and regurgitation into
plasma of bile constituents, impaired intracellular transport due to
cytoskeletal dysfunction, altered intracellular calcium homeosta-sis or altered
canalicular carriers (Erlinger, 1997). A recent study demonstrated that
oestrogen metabo-lites trans-inhibit the bile salt export pump in rat liver
providing a molecular basis for drug-induced cholestasis (Stieger et al., 2000).
Steatosis
Microvesicular
steatosis occurs in conditions char-acterised by severe impairment of the
mitochondrial β-oxidation process. Drugs can sequester co-enzyme A (aspirin
valproic acid), inhibit
mitochondrial β -oxidation
enzymes(tetracycline) and, in
addition, inhibit oxidative phosphorylation (amiodarone and perhexiline).
When β-oxidation
is severely impaired, fatty
acids, which are poorly oxidised by mitochondria, are mainly esterified into
riglycerides and accumulated as small vesicles (Fromenty, Berson and Pessayre,
1997).
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