844 SECTION X Liver Affected by Other Conditions or Diseases

56
Drug-Induced Liver Injury
HARSHAD DEVARBHAVI, H ERBERT L. BONKOVSKY,
MARK RUSSO, AND NAGA C HALASANI

A B B R E V I AT I O N S The multistep process for the metabolism of drugs and chemi-

ADR adverse drug reaction
ALF acute liver failure
ALT alanine aminotransferase
AP alkaline phosphatase
AST aspartate aminotransferase
ATP adenosine triphosphate
BHDS botanicals, herbal products, and dietary supplements
CI confidence interval
CYP cytochrome P450
DILI drug-induced liver injury
DILIN Drug-Induced Liver Injury Network
FDA Food and Drug Administration
GSH glutathione
HAART highly active antiretroviral therapy
HLA human leukocyte antigen
MMPT mitochondrial membrane permeability transition
NAPQI N-acetyl-p-benzoquinoneimine
NARTI nucleoside analog reverse transcriptase inhibitor
NSAID nonsteroidal antiinflammatory drugs
PI protease inhibitor
SOS sinusoidal obstruction syndrome
ULN upper limit of normal
Introduction
In humans and other higher organisms the liver is the principal
site for the metabolism of foreign substances. It is responsible
for absorbing, detoxifying, and excreting an astonishing array of
chemical substances, encountered both from outside the organism
(i.e., xenobiotics) and from within the organism, including many
substances synthesized by the liver itself. In the toxicology litera-
ture, there is a distinction between toxins, which are naturally
occurring poisons, and toxicants, which can be derived from any
source. In general, the liver and kidneys are chiefly responsible for
maintenance of the internal milieu of chemicals within narrow
concentration gradients. These organs also function to remove
potentially toxic compounds from organisms. In general, toxic
compounds of lower molecular weight and higher water solubil-
ity are excreted chiefly by the kidneys through glomerular filtra-
tion and/or tubular secretion. In contrast, larger, more lipophilic
substances must be absorbed and undergo initial metabolism by
the liver before their excretion either in the bile and feces or in
the urine.
cals is summarized in Fig. 56-1. Most such chemicals are ingested
orally and absorbed, chiefly in the proximal part of the small
intestine. Some of them undergo initial metabolism within the
gastrointestinal tract. Parent compounds and/or metabolites then
enter the splanchnic blood, from which they are eventually deliv-
ered by the portal circulation to the liver. Depending on the
xenobiotic in question, cells within the liver absorb a variable
proportion of the compound. This initial removal of compounds
from the portal blood, which is the chief blood supply to the liver,
is called the first-pass effect of the liver.
The uptake into liver cells occurs primarily, but not solely, into
hepatocytes. During the past several years a number of transport-
ers of cations and anions have been described and have been
identified as important in the uptake of endogenous chemicals
and xenobiotics (drugs, foreign chemicals) by liver cells. Once
inside hepatocytes, these chemicals undergo further intracellular
binding and transport. The intracellular mechanisms responsible
for such transport are less well understood. It is likely that highly
lipophilic compounds dissolve readily into the membranes of cells
and diffuse widely and quickly within and across such mem-
branes. In contrast, more hydrophilic compounds require protein
binding and other means for transport.
As shown in Fig. 56-1, many (but certainly not all) drugs and
chemicals require an initial oxidation reaction, termed phase I
metabolism. The most common example is hydroxylation cata-
lyzed by 1 of the 57 varieties of cytochrome P450 (CYP). Many
of these CYPs are found in hepatocytes, and they perform hydrox-
ylation reactions in concert with NADPH (as a source of elec-
trons) and cytochrome P450 reductase; for some chemicals,
cooperation with another heme-containing protein, cytochrome
b5, is also required. These enzymes and reactions occur principally
in the smooth endoplasmic reticulum.
Following the initial hydroxylation reaction, one of several
additional reactions leads to the addition of more water-soluble
moieties to the initial hydroxylated product. The enzymes
responsible for this so-called phase II metabolism are chiefly
glucuronosyltransferases, sulfotransferases, and enzymes that add
glutathione (GSH) or products of the reduced thiol form of
GSH (e.g., glutathione transferases). The key substrates for these
conjugation reactions are uridine diphosphoglucuronic acid, 3′-
phosphoadenosine 5′-phosphosulfate, and reduced GSH (the tri-
peptide L-γ-glutamyl-L-cysteinylglycine).
The third phase of hepatic drug metabolism—the transport of
the parent drug and/or its metabolites out of hepatocytes—can
occur in one of the following ways: drugs and/or metabolites
can be transported across the plasma membrane, with eventual

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