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Amacher 1998
Amacher 1998
Amacher 1998
asymptomatic. A fairly large number of drugs fall results. In humans, the incidence of fatty liver disease
within this category. These are not typically discon- noted at autopsy for accident victims ranges from 40
tinued for this phenomenon alone. For example, the to 80% (Hodgson et al., 1989) suggesting a high inci-
U.S. Physicians’ Desk Reference indicates that liver en- dence from unknown causes in the general adult popu-
zyme elevations may be found in up to 15% of patients lation. Necrotic cell death is accompanied by a disrup-
taking nonsteroidal anti-inflammatory drugs (NSAIDs). tion of cell membrane integrity and the loss of liver-
One NSAID in particular, sulindac, actually accounts specific enzymes which forms the basis of the serum
for most of the risk (Fry and Seeff, 1995; Garcia Rodri- chemistry analyses used systematically for its detec-
guez et al., 1994). Another example is the 12% inci- tion. Clinical manifestations of hepatic necrosis and
dence of asymptomatic hepatic enzyme abnormalities degeneration range from jaundice to fulminant hepatic
reported in ketoconazole recipients (Mosca et al., 1985). failure. Cholestatic injury occurs when there is a dis-
The disease under treatment may also affect the liver ruption or impairment of bile flow. Canalicular chole-
adversely leading to elevated hepatic enzymes. Most of stasis can be caused by several mechanisms including
these reactions are host-dependent, idiosyncratic re- leaky paracellular junctions, a diminished contractility
sponses which are not easily predicted in preclinical of canaliculus, diminished transcytosis, impaired
testing or observed in early clinical trials because of transporters, and toxin concentration in the paracani-
the small number of subjects. cular area (Moslen, 1996). Toxins or their metabolites
The final stage involves similar findings in a large can also damage the intrahepatic bile ducts. Chlor-
postmarketing population. These cases involve very- promazine, oral contraceptives, and androgens used to
low-frequency, idiosyncratic (type B) events that are increase muscle mass can produce a cholestatic re-
not detectable in controlled clinical populations of 500– sponse. Hepatobiliary lesions lead to elevated serum
1000, for example, due to mathematical probability. levels of bile constituents or enzymes localized in the
These result from a novel aspect of the patient, not the hepatobiliary tree such as Alk P or gamma glutamyl-
drug, and are more uncertain in etiology because they transpeptidase (GGT; EC 2.3.2.2). In humans, most he-
are typically reported in an uncontrolled nonclinical patic drug reactions appear within 3 months of starting
setting. Thus, drug-induced hepatic injury ranges from therapy (Davis, 1989).
frequent, dose-related effects in multiple species to rare
but profound hepatic effects only detectable in suscepti- 3. BIOCHEMICAL TESTS USED FOR THE DETECTION
ble individuals at therapeutic doses. Serum transami- OF HEPATIC INJURY
nase activities are the single diagnostic indicator for
all of these effects and are the subject of this review. 3.1. Categories of Laboratory Tests
2. HISTOLOGICAL TYPES OF TOXIC HEPATIC INJURY Three categories of noninvasive laboratory tests are
used to identify the type and extent of drug hepatotox-
In general, the type and degree of acute toxic liver icity based on the presence or absence of specific mark-
injury following drug administration depend upon the ers in the blood of exposed individuals. The first cate-
dose and duration of exposure. In addition, many chem- gory of clinical assays is that used to assess hepatocel-
icals preferentially affect certain cell populations but lular damage leading to liver cell necrosis. Evidence of
not others in the same host. Major histologic lesions of this type of injury is based on the detection the hepatic
the liver due to chemical toxicity include fatty change, transaminases, alanine aminotransferase (ALT), and
hepatocellular death, and hepatobiliary lesions. Gran- aspartate aminotransferase (AST). These are not nor-
ulomatous and mixed histological changes may also be mal components of blood and serve no known function
seen (Pirmohamed et al., 1992) or venoclusive effects, outside the organ of origin. A third specific marker of
especially with some antineoplastic drugs (McDonald hepatocellular damage, serum F protein, has been re-
and Tirumali, 1984). Steatosis or fatty change refers cently described (Foster et al., 1989), although it is not
to an increase in hepatic lipid content greater than 5% yet as widely used as the transaminases. Based on liver
by weight (Moslen, 1996). Lipid accumulates as intra- biopsy specimens, chronic ALT elevations in asymp-
cytoplasmic vacuoles in either a zonal or diffuse pat- tomatic patients have also been associated with fatty
tern. Microvesicular and macrovesicular steatoses, dif- liver (Hulteranz et al., 1986). In fact, nonalcoholic
fering in the lipid vacuole size and the mechanism for steatosis has been cited as a very common cause of
their formation, are distinguishing characteristics of chronic ALT elevations in the general population
specific toxicants. Macrovesicular steatosis is charac- (Craxi and Almasio, 1996). Thus, transaminase eleva-
terized by a single large fat droplet which displaces tions are indicative of hepatocellular death and fatty
the nucleus to the cell periphery, but in microvesicular degeneration in particular, but can also be used in con-
steatosis there are a number of small lipid droplets junction with other serum enzymes for distinguishing
that do not displace the nucleus (Stricker, 1992a). non-hepatocellular injury as described below.
Steatosis is reversible unless it is persistent enough to The second group of tests includes markers for hepa-
cause secondary changes or so severe that cell death tobiliary (chlolestatic) effects. This type of injury in-
hepatocellular injury for preclinical animal studies, chronic hepatitis, steatosis, metabolic diseases (Fregia
clinical trials, and postmarketing monitoring. et al., 1994), alcoholic liver disease, and, much less fre-
quently, drug-induced liver disease and nonalcoholic
3.2.2. AST. AST (EC 2.6.1.1) is found in both the steatosis (Renner and Dallenbach, 1992). In addition,
cytosol and mitochondria of hepatocytes (Herlong, some disease states, especially malignancies, produce
1994), but high tissue levels are also found in heart, hepatic effects culminating in elevated transaminases.
skeletal muscle, kidney, brain, and pancreas (Rej,
1989). Accordingly, muscle trauma and surgery by it-
5. GUIDELINES FOR SERUM TRANSAMINASE
self can lead to AST serum elevations (Clermont and
ELEVATION AS AN INDICATOR OF LIVER INJURY
Chalmers, 1967). An estimated 60–70% of AST activity
in human hepatocytes is localized within mitochondria By international consensus, liver injury, as might be
(Schmidt and Schmidt, 1990). Hence, when found in detected by liver tests, has been defined as an increase
blood, AST is considered to be a sensitive indicator of greater than two times the upper limit of normal range
mitochondrial damage, especially in the hepatic centri- (ULN) in ALT or conjugated bilirubin or a combined
lobular regions which are particularly sensitive to toxic increase in AST, Alk P, and total bilirubin provided
and hypoxic liver injury (Schmidt and Schmidt, 1990). that one of them is greater than two times the ULN
It should be noted, however, that depending upon the (Benichou, 1990). This injury is further defined as he-
assay used a number of drugs can reportedly produce patocellular when (1) there is an increase of greater
spurious elevations in AST (Davis, 1989). Serum AST than two times the ULN for ALT alone or (2) there is
is affected to a greater degree by alcohol consumption a ratio of serum ALT activity/serum Alk P activity
than ALT (Lewis, 1984). Within these limitations, AST greater than five or cholestatic when there is an in-
in conjunction with ALT is a very important marker of crease of greater than two times the ULN of Alk P
hepatic injury. alone or a ratio equal or less than two. Acute liver
injury is distinguished from chronic liver injury when
4. NON-DRUG-RELATED TRANSAMINASE ELEVATIONS the increases have lasted less or more than 3 months,
respectively. Severe liver injury and fulminant liver
The term transaminitis has been applied to mild ele- injury are defined by (1) the presence of jaundice, pro-
vations of serum aminotransaminases in the absence thrombin õ50% (or equivalent), and hepatic encepha-
of other clinical laboratory abnormalities in asymptom- lopathy and (2) the rapid development of hepatic en-
atic individuals (Hodgson et al., 1989; Rej, 1989). When cephalopathy and severe coagulation disorders, respec-
observed after drug exposure, these small elevations tively.
are often considered as being uninterpretable. A second
difficulty in monitoring transaminase levels in patient 6. SERUM ENZYME ELEVATIONS DUE TO HEPATIC
populations is the underlying incidence of mildly ab- ENZYME INDUCTION
normal results in a classical panel of liver tests used
in routine monitoring of asymptomatic, unaffected in- Enzyme induction is one reported iatrogenic effect
dividuals. These may be associated with population leading to elevated hepatic serum enzyme levels in pa-
characteristics previously discussed and are not usu- tient populations that are not directly indicative of he-
ally encountered in preclinical animal toxicology stud- patic injury. This has been well documented, especially
ies. Liver injury tests are abnormal in up to 8% of a for anticonvulsants, but also for some other drugs. In
healthy population (Hodgson et al., 1989). Liver en- one such study, 56 children of 63 receiving phenobarbi-
zyme elevations noted during hospital admission have tal and/or diphenylhydantoin had elevated GGT; 6 had
been estimated at 5.7–7.6% (Grohmann et al., 1984; elevated ALT and AST for more than 20 weeks in the
Van Dijke et al., 1986). In one study, 25–30% of asymp- absence of specific histopathology (Aiges et al., 1980).
tomatic, normal workers had serum chemistries on a Further evidence of hepatic enzyme induction by anti-
five-test liver panel in excess of the established normal convulsants in asymptomatic patients was cited by
range in the absence of risk factors for liver disease Wall et al. (1992) in a study of 206 adults and children.
(Wright et al., 1988). Of course, specific estimates of Of these, serum GGT was elevated in 74.6%, Alk P in
the incidence of abnormal ALT values alone are lower 29.7%, and ALT in 25.2%. Of 242 patients administered
in donor populations. In one study, the frequency of antiepileptic drugs, 40 exhibited high levels of serum
elevated ALT in a donor population was reported to GGT and nearly all cases indicated hepatic microsomal
be 4.6% above 40 IU/liter in 1986 and appeared to be enzyme induction as measured by antipyrine half-life,
increasing with time (Mijovic et al., 1987). In the ab- leading Hirayanagi et al. (1991) to conclude that, in
sence of any intentional drug exposure, extremely high these patients, elevated serum GGT did not necessarily
transaminase levels (ú8- to 10-fold normal) in a patient indicate hepatocellular damage. Elevated circulating
population may indicate acute viral hepatitis, drug- or levels of GGT are commonly observed in patients tak-
toxin-mediated liver necrosis, or other damage; persis- ing cytochrome P450 enzyme-inducing drugs such as
tent mild elevations (2- to 8-fold) are characteristic of rifamicin (Davis, 1989). Similar studies with co-antiep-
tions of the NAT2 gene are known to define numerous a generalized type of idiosyncratic drug reaction medi-
alleles associated with decreased function, and two mu- ated through the immune system may also involve the
tant alleles of CYP2C19 have been described in poor liver (Uetrecht, 1988).
metabolizers (Meyer and Zanger, 1997; Goldstein and
de Morias, 1994). Oxidative polymorphism for cyto- 7.3. Mixed or Species-Relevant Toxicity
chrome CYP2D6, which metabolizes drugs typically
having a positively charged nitrogen atom (Pirmo- Some drugs appear to cause idiosyncratic hepatic in-
hamed et al., 1996), includes poor, intermediate, and jury in humans and yet can also produce hepatotoxic-
ultrarapid metabolizers (Meyer and Zanger, 1997) ity, perhaps by a different mechanism, in animal mod-
leading to a wide range of interindividual variability els at high doses. Thus, the same drug can be an intrin-
in CYP2D6-based response in a healthy population sic hepatotoxicant in one or more animal models and
(Spina et al., 1994). For example, patients receiving the yet cause an idiosyncratic liver response in some hu-
antianginal agent perhexiline maleate who are defi- mans. Some of the angiotensin-converting enzyme in-
cient in CYP2D6 can develop hepatotoxicity due to per- hibitors used for the treatment of hypertension and
hexiline accumulation (Morgan et al., 1984). Although congestive heart disease fall into this category. Capto-
it is not subject to genetic polymorphism (Ereshefsky, pril, for example, has been associated with the rare
1996), both genetic and nongenetic factors lead to incidence of hepatotoxicity in humans (Rahmat et al.,
marked (5- to 20-fold) individual variability in meta- 1985; Tabibian et al., 1987). In mice, acute high doses
bolic clearance via CYP3A (Wilkinson, 1996) which of captopril cause moderate increases in ALT, de-
comprises 25% of the total hepatic cytochrome system. creases in hepatic GSH, and histological evidence of
This leads to wide variations in individual exposure hepatic necrosis with 24 h (Helliwell et al., 1985). Ena-
levels to drugs such as cyclosporine (Watkins, 1990). lapril maleate which has been reported to cause a rare
Polymorphism has also been described for CYP2C9 and but potentially serious hepatotoxicity in humans, was
CYP2E1 (Meyer and Zanger, 1997). The latter is im- demonstrated by Jurima-Romet and Huang (1992) to
portant for the metabolism of general anesthetics such produce centrilobular necrosis and significant moder-
as halothane which causes hepatitis in 1 in 35,000 pa- ate increases in ALT and AST 24 h after acute exposure
tients on first exposure and in 1 in 3700 patients upon in Fisher 344 rats.
multiple exposures (Pirmohamed et al., 1996).
8. THERAPEUTIC CLASS AND DRUG-INDUCED
7.2.2. Immune system-based toxicity. Immune- HEPATIC INJURY
based injuries represent the other major mechanism
for idiosyncratic responses in humans. Autoimmunity The frequencies of drug-induced hepatitis at thera-
triggered by xenobiotics involves the modification of peutic doses vary among drug classes with some classes
host tissues or immune cells by the chemical so that more consistently demonstrating low levels of hepatic
self-antigens are erroneously targeted; drug hypersen- injury than others. These can vary from 1/100 for a few
sitivity or allergy refers to a situation where the im- compounds, to 1/10,000 for some intermediate com-
mune system responds in an exaggerated or inappro- pounds, to 1/100,000 for others (Larrey and Pageaux,
priate manner (Burns et al., 1996) by one of four mecha- 1997). For one antitumor antibiotic, elevations of ami-
nisms (Combs and Gell, 1975). Most autoimmune notransferases can occur in up to 100% of patients
diseases are associated with specific alleles of the major (King and Perry, 1995). In one large study (Sameshima
histocompatibility complex (MHC) class II genes (Fro- et al., 1984) based on 8156 case histories of drug-in-
nek et al., 1991). The high level of polymorphism that duced hepatic injury over a 70-year period in Japan,
is characteristic of the MHC genes may lead to subpop- the greatest number of cases was due to antibiotics
ulations of individuals who are highly immune to re- (34%), followed by CNS drugs (15%), chemotherapeutic
sponses toward drug-related antigens (Park et al., drugs (14%), cardiovascular drugs (11%), carcinostatic
1992). Four major categories of drugs known to cause drugs (7%), hormones and hormone antagonists (6%),
autoimmune responses include hydrazines, derivatives diagnostic aids (4%), and other drugs (9%). A smaller
of aromatic amines, sulfhydryl-containing compounds, study based on 46 patients representing 20% of pa-
and compounds with a phenol ring (Adams and Hess, tients admitted for acute or chronic hepatitis during
1991). Specific examples of drugs known or suspected a 3-year period cited anti-inflammatories, antibiotics,
of causing hepatitis via an autoimmune mechanism antihypertensives, and diuretic drugs as being most
include methyldopa, oxypehnisatin, isoniazid, nitrofu- frequently implicated (Grippon et al., 1985). In the U.S.
rantoin, clometacin, fenofibrate, papaverine, and tie- Physicians Desk Reference, transaminase elevations,
nilic acid (Bigazzi, 1988). Although other nongenetic albeit usually minor and infrequent, are not uncommon
factors may be involved in the etiology of altered im- for drugs classified as antineoplastic compounds, neu-
mune responses, the role of drug metabolism polymor- rotrophic drugs, and antibiotics/antibacterials. Table 1
phism leading to bioactivation is an important one. Ex- summarizes available information for some of these
trahepatic metabolism of some drugs associated with drug categories.
Nonsteroidal Incidence of acute liver injury is about 3.7 Mostly idiosyncratic responses. Garcia Rodriguez et al. (1994),
anti-inflammatory per 100,000 NSAID users. Transaminase Boelsterli et al. (1995)
drugs levels abnormal in 5–15% of patients
taking a particular drug.
Anticancer drugs Hepatotoxic manifestations include Diverse injuries, both intrinsic King and Pery (1995),
venoclusive disease, hepatocellular and idiosyncratic. McDonald and Tirumali
necrosis, and fatty change. Incidence of (1984), Jean-Paston and
1.3% in 980 cases of hepatic injury in one Jouaglard (1984)
study.
Antibacterials Estimated frequency of hepatotoxic Injuries include necrosis, George and Crawford (1996),
reactions is between 1 and 10 per 100,000 cholestasis, cholangitis, and Stricker et al. (1992b),
drug prescriptions. Antibiotics accounted other. Mostly idiosyncratic Stricker (1986)
for one-third of all suspected drug- except intrinsic for
induced hepatic injury in one study. Mild tetracyclines and some
transient transminase elevations reported macrolides.
in up to 30–50% of recipients for some
antibiotics.
Cardiovascular In one study, cardiovascular agents were Autoimmune or hypersensitivity Jean-Pastor and Jouglard
implicated in 27.3% of 980 cases of liver reactions with antiarrhythmic (1984), Stricker et al.
injury. Diuretics accounted for 13.9% in agents; heptocellular pattern (1992b), Stricker (1986)
another study. Mild ALT/AST elevations with antihypertensive agents.
are common at the onset of treatment.
9. DRUGS FREQUENTLY ASSOCIATED man populations are affected by a variety of both ge-
WITH HEPATOTOXICITY netic and environmental factors. In addition, some se-
rum enzymes of hepatic origin used for assessment of
Some marketed drugs have been associated with a liver injury or disease can be increased by hepatic en-
high, predictable incidence of suspected hepatotoxicity zyme induction instead of or in addition to membrane
in human populations, as, for example, they may cause leakage caused by hepatic damage. Within these limi-
asymptomatic, transient elevations in serum transami- tations, guidelines for the detection of hepatic injury
nase levels in ¢10% of the patient population. It should via these biochemical markers have been established.
be noted that the actual frequency of isolated, asymp- The hepatic metabolism of drugs to reactive toxicants
tomatic elevations of transaminases in patient popula- or protein-binding moieties is the single most im-
tions may actually be understated because liver func- portant, but by no means the only mechanism leading
tion tests are not routinely ordered during routine clini- to hepatic injury. Unlike preclinical laboratory animals
cal practice (Jick, 1995). Some examples are shown in which are relatively homogenous in terms of their con-
Table 2. Likewise, drug interaction, disease complica- stitutive hepatic cytochrome P450 isozymes, human
tions, viral infections, or combinations of drugs may be populations are remarkably diverse with cytochrome
responsible, in part, for some of these effects. P450 enzyme polymorphisms and other individual dif-
ferences in drug-metabolizing enzyme systems being
10. DISCUSSION prevalent. Subtle individual differences in the hepatic
detoxification processes or the formation of minor but
Drug-induced liver toxicity can be detected at various highly reactive metabolites in susceptible individuals
stages of drug development depending upon the mecha- can lead to rare but unpredictable consequences as an
nism responsible for hepatic injury. Intrinsic hepato- increasing proportion of the population is exposed to a
toxicants are effectively identified in the preclinical drug at therapeutic doses. Frequently, these idiosyn-
testing stage using animal models at doses much cratic responses are caused by an aberrant immune
higher than the intended human dose while, at the response to the drug or a drug-altered self-antigen. For
other extreme, rare but sometimes fatal idiosyncratic both direct, intrinsic toxic responses in humans or labo-
responses can only be discovered after the exposure of ratory animals and isolated idiosyncratic responses in
thousands of patients to therapeutic levels of the drug. a clinical setting, early evidence of hepatic injury is
Elevated serum transaminases, especially ALT, are the obtained via biochemical methods including the moni-
single most important laboratory indicators of hepatic toring of serum transaminases.
effects from early preclinical testing to the postmarket While knowledge of the typical human metabolism
monitoring of patients responding to a variety of histo- of experimental drugs will not predict idiosyncratic he-
logic effects. Baseline serum transaminase levels in hu- patic toxicity, it can be useful in determining similari-
TABLE 2
Drugs Frequently Associated with Elevated Transaminase Levels
Amiodarone Approximately 25% of users Phospholipidosis. Metabolic idiosyncratic. Lewis et al. (1989),
(antiarrhythmic) develop transminase Sticker et al. (1992)
elevations ú2 times normal
during treatment.
Chlorpromazine Mild liver enzyme elevations Cholestatic or mixed. Reactive metabolite Davis (1989), Pessayre
(anticonvulsant) in 10–42% of recipients; responsible, (1992), De Mol et al.
serum transaminases imunoallergy. (1984), Stricker et al.
typically elevated first week (1992b)
of treatment.
Cognex (tacrine–HCl) Elevated transaminases (ú3 Consistent with Mechanism of Watkins et al. (1994)
cholinesterase times upper limit of normal) hepatocellular injury. hepatotoxicity is
inhibitor (cognition in 25% of patients. unclear.
activator)
Ibufenac Elevated transaminase levels Hepatocellular necrosis. Intrinsic toxicity. Boelsterli et al. (1995),
(nonsteroidal anti- in ú30%; hepatocellular Removed from clinical Fry and Seeff (1995)
inflammatory) jaundice in 5% of use in 1967.
individuals.
Iproniazid Abnormal transaminases in up Hepatocellular necrosis. Reactive metabolite Sticker et al. (1992b)
(antidepressant) to 20% of recipients. Withdrawn from most
markets.
Isoniazid Serum transaminases elevated Liver injury reported in Reactive metabolite Davis (1989), Timbrell
(antibacterial) in 10–20% of patients. 0.5% of adults; higher responsible for et al. (1980), Stricker
in children metabolic (1986), Stricker et al.
idiosyncratic (1992b), PDR
response.
a-Methyldopa Transient increases in Acute hepatitis in about Reactive metabolite Davis (1989), Finlayson
(antihypertensive) transaminases, Alk P, 6% of patients within responsible, (1973), Dybing et al.
bilirubin in 2.8% of patients. the first few weeks. hypersensitivity. (1976)
Naltrexone–HCl Peak ALT levels 3–19 times No cases of hepatic Direct hepatotoxin. PDR
(Revia) (opioid baseline values in some failure reported.
antagonist) patients after 3–8 weeks of
treatment.
Precose (acarbose) ALT and/or ALT elevated ú3 Hepatic abnormalities Not reported. PDR
a-glucosidase times upper limit of normal improved or resolved
inhibitor (diabetes) in 15% of patients. upon discontinuation.
a-Methyldopa Transient increases in Acute hepatitis in about Reactive metabolite Davis (1989), Finlayson
(antihypertensive) transaminases, Alk P, and 6% of patients within responsible, (1973), Dybing et al.
bilirubin in 2.8% of patients. the first few weeks. hypersensitivity. (1976)
Naltrexone–HCl Peak ALT levels 3–19 times No cases of hepatic Direct hepatotoxin. PDR
(Revia) (opioid baseline values in some failure reported.
antagonist) patients after 3–8 weeks of
treatment.
Precose (acarbose) ALT and/or ALT elevated ú3 Hepatic abnormalities Not reported. PDR
a-glucosidase times upper limit of normal improved or resolved
inhibitor (diabetes) in 15% of patients. upon discontinuation.
Proleukin Elevated in 56% of patients. Elevated bilirubin, Not reported. PDR
(aldesleukin; alkaline phosphatase,
interleukin-2 jaundice.
product)
(anticancer)
Riluzole (Rilutek) Elevated ALT in 10% and AST Dose-related (intrinsic). Bryson et al. (1996)
(amyotrophic in 14% of patients at 100
lateral sclerosis mg/kg.
treatment)
Tienilic acid AST and ALT elevated. 1 in 10,000 patients Reactive metabolite Dansette et al. (1991),
(uricosuric diuretic) develop hepatitis of responsible, Stricker (1986)
the immunoallergic immunoallergy.
type. Withdrawn from
the market.
Valproic acid Frequent, minor, dose-related Microvesicular steatosis Reactive metabolite. Koch-Weser and Browne
(anticonvulsant) elevations of ALT, AST, and (1980), Pessayre (1992),
LDH reported. Porubek et al. (1984),
PDR
multiple human cytochromes during the preclinical Coombs, R. R. A., and Gell, P. G. H. (1975). Classification of allergic
testing phase may enhance our ability to anticipate reactions responsible for clinical hypersensitivity and disease. In
Clinical Aspects of Immunology (P. G. H. Gell, R. R. A. Coombs,
both intrinsic and idiosyncratic toxic responses. and P. G. Lachmann, Eds.), pp. 761–781. Oxford Univ. Press, Ox-
• Although the monitoring of serum transaminases ford.
will continue to be an important clinical laboratory pro- Craxi, A., and Almasio, P. (1996). Diagnostic approach to liver en-
cedure for the assessment of preclinical hepatotoxicity, zyme elevation. J. Hepatol. 25(Suppl. 1), 47–51.
new developments involving comparative toxicity Dansette, P. M., Amar, C., Valadon, P., Pons, C., Beaune, P. H., and
assays in human and animal hepatocyte cultures, tech- Mansuy, D. (1991). Hydroxylation and formation of electrophilic
metabolites of tienilic acid and its isomer by human liver micro-
niques to detect altered gene expression or changes in somes. Biochem. Pharmacol. 41, 553–560.
protein structure and abundance, or improved methods
Davis, M. (1989). Drugs and abnormal ‘liver function tests.’ Adverse
for the detection of immunogenicity will augment the Drug React. Bull. 139, 520–523.
safety assessment process. De Mol, N. J., and Busker, R. W. (1984). Irreversible binding of the
chlorpromazine radical cation and of photoactivated chlorproma-
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