Mechanisms of Drug-Induced Liver Disease

doi:10.1016/j.cld.2007.06.001

Clinics in Liver Disease

Volume 11, Issue 3, August 2007, Pages 459-475

https://doi.org/10.1016/j.cld.2007.06.001 Get rights and content

Drug-induced liver injury depends initially on development of hepatocyte stress and cell death, which can be induced directly by parent drugs or by toxic metabolites. Hepatocyte stress can lead to activation of built-in death programs for apoptosis or necrosis. Subsequently, the innate immune system's participation is recruited. The interplay between proinflammatory and anti-inflammatory components of innate immune system determines the outcome of drug-induced liver injury. Both environmental factors and genetic differences in cellular responses to stress and the innate immune response may account for different susceptibilities between individuals to drug-induced liver injury.

Section snippets

Types of drug-induced liver injury

Drug-induced liver injury can be predictable; it is normally dose-dependent, reproducible in animal models, and presents after a short latency (hours to a few days). Drugs that cause this type of liver injury are usually identified during initial toxicology studies. These findings typically preclude further use as medication. Most drug-induced liver injuries, however, are unpredictable or idiosyncratic, although they may or may not be dose-dependent or reproducible in animal models [2], [3], [4]

Drug metabolism in the liver

The liver is the principal organ for metabolism and elimination of many drugs. Even though some drugs cause hepatotoxicity when the parent compound directly targets specific organelles, such as mitochondria or nuclei, most toxic drugs require metabolism to toxic metabolites [2]. There are three phases of drug metabolism in the liver. In phase I, drugs are metabolized by cytochrome P-450 enzymes. This process can generate toxic electrophilic chemicals and free radicals. In phase II, the parent

Biochemical events leading to drug-induced liver injury

The toxic metabolites from drug metabolism can then either directly affect the biochemistry of the liver cells leading to cell damage or elicit an immune-mediated attack on the liver [4]. Drug metabolites can covalently bind to proteins, lipids, and DNA, and mediate cell death by inciting biochemical events, such as oxidative stress, GSH depletion, and redox changes, and lipid peroxidation. Consequently, these events may directly affect the functions of mitochondria, endoplasmic reticulum,

Mode of cell death

The outcome of the events initiated by toxic metabolites either through directly affecting the biochemistry in hepatocytes or immune-mediated response is cell death. The mode of cell death may be apoptosis or necrosis. Apoptosis involves shrinkage, nuclear disassembly, and fragmentation of the cell into discrete bodies with intact plasma membranes. The apoptotic cells are then rapidly phagocytosed by neighboring cells. In contrast, necrosis involves cell swelling and lysis as a result of

Role of innate immune system

The innate immune system has been implicated in hepatotoxicity caused by various drugs, such as APAP, dihydralazine, and halothane [6], [22]. Studies have demonstrated that the liver injury caused by hepatotoxins can be associated with participation of increased numbers of proinflammatory mediators, such as cytokines, chemokines, reactive oxygen intermediates, and reactive nitrogen intermediates [22]. These proinflammatory mediators can be directly cytotoxic (eg, hydrogen peroxide, nitric

Acetaminophen: an example of drug hepatotoxicity

APAP is the most extensively studied hepatotoxin and provides the bulk of knowledge on drug hepatotoxicity. The current understanding of the mechanism of its hepatotoxicity is described next as an example, illustrating some of the key aspects of the pathogenesis of drug-induced liver injury. APAP is primarily metabolized in the liver by glucuronidation and sulfation pathways into nontoxic metabolites that are then excreted in the urine. A small amount of APAP is metabolized by oxidation,

Role of innate immune system in acetaminophen hepatotoxicity

The severity of APAP liver injury may be influenced by the innate immune system. It is well established that hepatocellular necrosis can induce an inflammatory response [24]. Recent studies have demonstrated that chromatin protein high mobility group box-1 released from necrotic cells can trigger inflammatory response, and neutralization of high mobility group box-1 leads to decreased APAP-induced inflammatory cell infiltration in the liver [67], [68]. It has also been shown that APAP-induced

Summary

It seems that the biochemical changes in hepatocytes (eg, GSH depletion and covalent binding) or immune-mediated response induced by toxic metabolites are required to cause hepatotoxicity. Toxic metabolites may induce intracellular stress (oxidative or organelle specific) leading to the activation of built-in death programs for apoptosis or necrosis. The participation of innate immune system downstream of the biochemical events induced by toxic metabolites contributes to the severity of liver

References (105)

N. Kaplowitz
Causality assessment versus guilt by association in drug hepatotoxicity
Hepatology
(2001)
Z.X. Liu et al.
Immune-mediated drug-induced liver disease
Clin Liver Dis
(2002)
S.R. Knowles et al.
Idiosyncratic drug reactions: the reactive metabolite syndrome
Lancet
(2000)
M.A. Robin et al.
Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis
J Hepatol
(1997)
D.L. Laskin et al.
Role of macrophages and inflammatory mediators in chemically induced toxicity
Toxicology
(2001)
S.S. Lee et al.
Role of CYP2e1 in the hepatotoxicity of acetaminophen
J Biol Chem
(1996)
M.A. Gerber et al.
Acetaminophen associated hepatic injury: report of two cases showing unusual portal tract reactions
Hum Pathol
(1980)
H. Okawa et al.
Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity
Biochem Biophys Res Commun
(2006)
L.L. Meyers et al.
Acetaminophen-induced inhibition of mitochondrial respiration in mice
Toxicol Appl Pharmacol
(1988)
H. Jaeschke et al.
The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity
Toxicol Lett
(2003)

P.C. Burcham et al.

Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes

J Biol Chem

(1991)

S.D. Cohen et al.

Selective protein covalent binding and target organ toxicity

Toxicol Appl Pharmacol

(1997)

B. Gunawan et al.

c-Jun-N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity

Gastroenterology

(2006)

T. Uehara et al.

JNK mediates hepatis ischemia perfusion injury

J Hepatol

(2005)

H. Kamata et al.

Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinases phosphatases

Cell

(2005)

K. Sabapathy et al.

Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation

Mol Cell

(2004)

S. Kharbanda et al.

Translocation of SAPK/JNK to mitochondria and interaction with Bcl-XL in response to DNA damage

J Biol Chem

(2000)

M. Fan et al.

Vinblastine-induced phosphorylation of Bcl2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade

J Biol Chem

(2000)

H. El-Hassan et al.

Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases

Toxicol Appl Pharmacol

(2003)

P.B. Limaye et al.

Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants

Toxicol Appl Pharmacol

(2003)

Z.X. Liu et al.

Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity

Gastroenterology

(2004)

M.E. Blazka et al.

Role of proinflammatory cytokines in acetaminophen hepatotoxicity

Toxicol Appl Pharmacol

(1995)

P.J. Ferret et al.

Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse

Hepatology

(2001)

D.M. Dambach et al.

Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse

Hepatology

(2002)

M. Bourdi et al.

Protection against acetaminophen induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase

Hepatology

(2002)

Y. Masubuchi et al.

Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease

Biochem Biophys Res Commun

(2003)

C.M. Hogaboam et al.

Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2

Am J Pathol

(2000)

D.L. Laskin et al.

Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen

Hepatology

(1995)

G.S. Smith et al.

Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats

J Surg Res

(1998)

G. Ostapowicz et al.

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

Ann Intern Med

(2002)

B. Gunawan et al.

Clinical perspectives on xenobiotic-induced hepatotoxicity

Drug Metab Rev

(2004)

N. Kaplowitz

Biochemical and cellular mechanisms of toxic liver injury

Semin Liver Dis

(2002)

N. Kaplowitz

Idiosyncratic drug hepatotoxicity

Nat Rev Drug Discov

(2005)

J. Uetrecht

New concepts in immunology relevant to idiosyncratic drug reactions: the danger hypothesis and innate immune system

Chem Res Toxicol

(1999)

P. Matzinger

Tolerance, danger, and extended family

Annu Rev Immunol

(1994)

L.A. Ozick et al.

Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients

Am J Gastroenterol

(1995)

W.M. Wong et al.

Antituberculous drug-related liver dysfunction in chronic hepatitis B infection

Hepatology

(2000)

J.E. Ungo et al.

Antituberculous drug-induced hepatotoxicity: the role of hepatitis C virus and the human immunodeficiency virus

Am J Respir Crit Care Med

(1998)

F. Gordin et al.

Adverse reactions to trimethoprin-sulfamethoxazole in patients with the acquired immunodeficiency syndrome

Ann Intern Med

(1984)

M. Levy

Role of viral infections in the induction of adverse drug reactions

Drug Saf

(1996)

D. Vergani et al.

Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis

N Engl J Med

(1980)

J. Neuberger et al.

Immune mechanisms in tienilic acid associated hepatotoxicity

Gut

(1989)

K. Kon et al.

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Hepatology

(2004)

A. Ashkenazi et al.

Death receptors: signaling and modulation

Science

(1998)

W.A. Faubion et al.

Death receptors in liver biology and pathology

Hepatology

(1999)

M.C. Wei et al.

Pro-apoptotic Bax and Bak: a requisite gateway to mitochondrial dysfunction and death

Science

(2001)

D.L. Laskin et al.

Nonparenchymal cells, inflammatory macrophages, and hepatotoxicity

I.R. Mackay

Hepatoimmunology: a perspective

Immunol Cell Biol

(2002)

Z.X. Liu et al.

Role of innate immunity in acetaminophen-induced hepatotoxicity

Expert Opin Drug Metab Toxicol

(2006)

L. Bouwens et al.

Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver

Hepatology

(1986)

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Acetaminophen (APAP)–induced liver injury is influenced by inflammatory Gram-negative bacterial endotoxin [lipopolysaccharide (LPS)], mechanisms of which are not completely understood. Because LPS-stimulated perisinusoidal hepatic stellate cells (HSCs) produce cytokines that affect survival of hepatocytes, this study investigated their role in APAP-induced liver injury. Fed (nonstarved) rats were administered 5 mg/kg LPS or phosphate-buffered saline (PBS) vehicle, followed by 200 mg/kg APAP or PBS an hour later, and euthanized at 6 hours. Control rats received PBS at both time points. Both LPS and APAP caused mild hepatocyte injury (apoptosis), as assessed by histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and caspase-3 activation. The liver injury was augmented in rats administered LPS + APAP, in association with increased nuclear translocation of interferon-regulatory factor-1 (IRF1). In vitro, APAP augmented LPS/HSC-conditioned medium–induced inhibition of DNA and protein synthesis, apoptosis, and nuclear IRF1 in hepatocytes. LPS-stimulated HSCs produced interferon-β (IFN-β), and LPS/HSC + APAP-induced hepatocyte apoptosis was inhibited by anti–IFN-β antibody. Finally, HSC-depleted mice produced significantly lower IFN-β and tumor necrosis factor-α, exhibited less oxidative stress, and were protected from excessive injury due to high APAP dose (600 mg/kg), as well as LPS (5 mg/kg overnight) followed by APAP. In co-culture with or without LPS, HSCs increased expression of proinflammatory cytokines by Kupffer cells. These results suggest that HSCs play a critical role in APAP-induced liver injury without or with LPS preconditioning, and it involves INF-β–IRF1 signaling.
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Citation Excerpt :
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Mechanisms of Drug-Induced Liver Disease

Section snippets

Types of drug-induced liver injury

Drug metabolism in the liver

Biochemical events leading to drug-induced liver injury

Mode of cell death

Role of innate immune system

Acetaminophen: an example of drug hepatotoxicity

Role of innate immune system in acetaminophen hepatotoxicity

Summary

Hepatology

Clin Liver Dis

Lancet

J Hepatol

Toxicology

J Biol Chem

Hum Pathol

Biochem Biophys Res Commun

Toxicol Appl Pharmacol

Toxicol Lett

J Biol Chem

Toxicol Appl Pharmacol

Gastroenterology

J Hepatol

Cell

Mol Cell

J Biol Chem

J Biol Chem

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

Gastroenterology

Toxicol Appl Pharmacol

Hepatology

Hepatology

Hepatology

Biochem Biophys Res Commun

Am J Pathol

Hepatology

J Surg Res

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

Ann Intern Med

Clinical perspectives on xenobiotic-induced hepatotoxicity

Drug Metab Rev

Biochemical and cellular mechanisms of toxic liver injury

Semin Liver Dis

Idiosyncratic drug hepatotoxicity

Nat Rev Drug Discov

New concepts in immunology relevant to idiosyncratic drug reactions: the danger hypothesis and innate immune system

Chem Res Toxicol

Tolerance, danger, and extended family

Annu Rev Immunol

Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients

Am J Gastroenterol

Antituberculous drug-related liver dysfunction in chronic hepatitis B infection

Hepatology

Antituberculous drug-induced hepatotoxicity: the role of hepatitis C virus and the human immunodeficiency virus

Am J Respir Crit Care Med

Adverse reactions to trimethoprin-sulfamethoxazole in patients with the acquired immunodeficiency syndrome

Ann Intern Med

Role of viral infections in the induction of adverse drug reactions

Drug Saf

Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis

N Engl J Med

Immune mechanisms in tienilic acid associated hepatotoxicity

Gut

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Hepatology

Death receptors: signaling and modulation

Science

Death receptors in liver biology and pathology

Hepatology

Pro-apoptotic Bax and Bak: a requisite gateway to mitochondrial dysfunction and death

Science

Nonparenchymal cells, inflammatory macrophages, and hepatotoxicity

Hepatoimmunology: a perspective

Immunol Cell Biol

Role of innate immunity in acetaminophen-induced hepatotoxicity

Expert Opin Drug Metab Toxicol

Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver

Hepatology