Susceptibility Factors in Susceptibility Factors in Idiosyncratic Idiosyncratic Drug-Induced Liver Injury Drug-Induced Liver Injury Steven Yee Steven Yee Molecular and Cellular Toxicology Section Molecular and Cellular Toxicology Section National Institutes of Health National Institutes of Health [email protected][email protected]8 June 2004 8 June 2004 U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute
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Susceptibility Factors in Idiosyncratic Drug-Induced Liver Injury Steven Yee Molecular and Cellular Toxicology Section National Institutes of Health [email protected].
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Susceptibility Factors in IdiosyncraticSusceptibility Factors in IdiosyncraticDrug-Induced Liver InjuryDrug-Induced Liver Injury
Steven YeeSteven YeeMolecular and Cellular Toxicology SectionMolecular and Cellular Toxicology Section
National Institutes of HealthNational Institutes of [email protected]@nhlbi.nih.gov
8 June 20048 June 2004
U.S. Department of Healthand Human Services
National Institutes of Health
National Heart, Lung, and Blood Institute
• Occurs in small fraction of individualsOccurs in small fraction of individuals
• Difficult to predictDifficult to predict
• Major clinical problem; often life-threateningMajor clinical problem; often life-threatening • Leading cause of acute liver failureLeading cause of acute liver failure
• Reason drugs removed from clinical Reason drugs removed from clinical development and widespread usedevelopment and widespread use
Examples of Drugs Withdrawn Due to Examples of Drugs Withdrawn Due to Liver DiseaseLiver Disease
IproniazidIproniazid19561956
Ibufenac (in Europe only)Ibufenac (in Europe only)19751975
TicrynafenTicrynafen1979 1979
BenoxaprofenBenoxaprofen1982 1982
Perhexiline (in France)Perhexiline (in France) 19851985
Dilevalol (in Portugal, Ireland)Dilevalol (in Portugal, Ireland)19901990
BromfenacBromfenac 19981998
Troglitazone Troglitazone 20002000
SerzoneSerzone20042004
• Mechanism often involves drug metabolitesMechanism often involves drug metabolites– Affect critical biochemical functionsAffect critical biochemical functions– Specific immune responsesSpecific immune responses
• Only a few drugs demonstrate these Only a few drugs demonstrate these underlying causesunderlying causes
• Tissue susceptibility: imbalance between Tissue susceptibility: imbalance between protoxicants and protectantsprotoxicants and protectants
Hepatotoxicants Potentiated by Exposure to Hepatotoxicants Potentiated by Exposure to Small Doses of Lipopolysaccharide (LPS)Small Doses of Lipopolysaccharide (LPS)
XenobioticsXenobioticsCClCCl44
GalactosamineGalactosamine
EthanolEthanol
T2-toxinT2-toxin
CadmiumCadmium
HalothaneHalothane
LeadLead
Allyl AlcoholAllyl Alcohol
Aflatoxin BAflatoxin B11
ChlorpromazineChlorpromazine
RanitidineRanitidine
SourceSourceFormal Formal et al.et al., 1960, 1960
ExtensiveExtensiveLiver InjuryLiver InjuryAnd DeathAnd Death
Model CompoundModel Compound
• Many of the protective factors discovered through Many of the protective factors discovered through research on acetaminophen (APAP) toxicityresearch on acetaminophen (APAP) toxicity
• AcetaminophenAcetaminophen– Clinically relevant; analgesic, antipyreticClinically relevant; analgesic, antipyretic– Over 50,000 ER visits per yearOver 50,000 ER visits per year– 450 death per year450 death per year
– Unlike with drug idiosyncrasy, it is well characterized Unlike with drug idiosyncrasy, it is well characterized and reproducible in animalsand reproducible in animals
• Bioactivation to Bioactivation to NN-acetyl--acetyl-pp-benzoquinone imine -benzoquinone imine (NAPQI)(NAPQI)
Development of Hepatotoxicity in Mice Given Development of Hepatotoxicity in Mice Given IL-13 Neutralizing Antibody 2 Hours beforeIL-13 Neutralizing Antibody 2 Hours before
200 mg APAP/Kg 200 mg APAP/Kg
Ser
um
AL
T (
IU/L
)
0
1000
2000
3000
4000
______ ______ ______ 4 8 24
Hours After APAP Administration
a
CAb/APAPIL-13 NAb/APAP
a
a
Ser
um
IL
-13
(pg
/ml)
0
25
50
75
100
______ ______ ______ 4 8 24
Hours After APAP Administration
CAb/APAPIL13NAb/APAP
a a
Ser
um
AL
T (
IU/L
)
0
3000
6000
9000
12000
______ ______ ______ 4 8 24
Hours After APAP Administration
a
WTKO
a
a
Development of Hepatotoxicity in IL-13 KO Development of Hepatotoxicity in IL-13 KO Mice Treated With 200 mg APAP/Kg Mice Treated With 200 mg APAP/Kg
Liver Histopathology at 8 hoursLiver Histopathology at 8 hours
CVCV CVCV
CVCV
CVCV
CVCV
CVCV
CVCV
CVCV
CAb/VehCAb/Veh CAb/APAPCAb/APAP
IL-13 NAb/APAPIL-13 NAb/APAP APAP - KOAPAP - KO
Nitric Oxide PathwayNitric Oxide Pathway
L-Arginine
L-Ornithine
IL-4, IL-10, IL-13IL-4, IL-10, IL-13
IL-1, IL-6, IL-1, IL-6, TNF-TNF-IFN-IFN-γγ
NOiNOSiNOS
ArginaseArginase
Citrulline
Urea
L-NILAminoguanidine (AMG)
Nitrite/Nitrate
Peroxynitrite+Superoxide+Superoxide
• Endogenous IL-13 is a hepatoprotective Endogenous IL-13 is a hepatoprotective factor in APAP-induced liver injuryfactor in APAP-induced liver injury
• Elevated NO levels – causal role?Elevated NO levels – causal role?
• Deficiency in IL-13 may increase Deficiency in IL-13 may increase susceptibility to drug-induced liver susceptibility to drug-induced liver diseasedisease
• Underproduction of hepatoprotective and Underproduction of hepatoprotective and overproduction of hepatoprotoxicant overproduction of hepatoprotoxicant
factors (i.e., imbalance) influences factors (i.e., imbalance) influences susceptibility to this susceptibility to this liver diseaseliver disease
Determination of Susceptibility FactorsDetermination of Susceptibility Factors
• Identification of liver protoxicant and protectant Identification of liver protoxicant and protectant factors results in better understanding of factors results in better understanding of mechanism and in facilitating prediction of mechanism and in facilitating prediction of drug-drug-induced liver diseaseinduced liver disease