BIOCHEMICAL MECHANISMS OF DRUG TOXICITIES
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BIOCHEMICAL MECHANISMS OF DRUG TOXICITIES
Lance R. Pohl, Pharm.D., Ph.D.Chief, Section of Molecular and Cellular Toxicology Laboratory of Molecular [email protected]/4/2007
U.S. Department of Health and Human
Services
National Institutes of Health
National Heart, Lung, and Blood Institute
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TOXICITIES PRODUCED BY DRUGS
AnaphylaxisHemolytic anemiaGranulocytopeniaThrombocytopeniaAplastic anemiaVasculitis
HepaticSkinRenalPulmonaryCardiacNeurologicalLupus
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LEADING CAUSES OF DEATH IN USA IN 1994
Heart disease Cancer Stroke Adverse drug reactions Pulmonary disease Accidents Pneumonia Diabetes
Lazarou et al., JAMA, 279, 1208 (1998)
743,460 529,904 150,108 106,000 101,077 90,523 75,719 53,894
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TYPE A ADRs
• Accounts for 80% of ADRs• Dose-dependent and often predictable • Often due to excessive expression of
known pharmacologic effects• Often caused by drug-drug interactions• Often reproduced in animalsRole of transporters in drug interactions, C.J. Endres, et al., European Journal of
Pharmaceutical Sciences, 27, 501 (2006)
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EXAMPLES OF TYPE A ADRS
• Drowsiness from the use of antihistamines
• Exacerbated therapeutic responses of warfarin and phenytoin-low therapeutic indices
• Posicor, anti-hypertensive withdrawn from market because inhibited the metabolism of over 30 drugs
• Acetaminophen• Fialuridine
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FIALURIDINE-INDUCED MITOCHONDRIAL INJURY IN PATIENTS
• FIAU is a uridine analog developed for hepatitis B treatment
• Administration to 15 patients resulted in 7 developing severe mitochondrial liver damage with 5 dying and 2 receiving liver transplants
• Toxicity was not predicted from rodent studies• Toxicity of FIAU is apparently due to FIAU-TP which
inhibits mitochondrial DNA polymerase-γ and DNA synthesis
• Humans and not rodents have human nucleoside transporter 1 (hENT1) in the mitochondrial membrane
E.W. Lee, et al., J.Biol.Chem., 281, 16700 (2006)
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TYPE B ADRs
• Accounts for 20% of ADRs• Rare, unpredictable, and highly host-
dependent• Mechanisms usually unknown, but in some
cases they have been attributed to: Allergic reactions Pseudoallergic reactions Deficiency in cytoprotective factors Polymorphisms
• Rarely reproduced in animals
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HAPTEN HYPOTHESIS AND DRUG-INDUCED ALLERGIC REACTIONS
+ Drug orMetabolite
B and T C ell R esponsesT oxicity
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FORMATION OF PROTEIN ADDUCTS WITHOUT DRUG METABOLISM
R CH2
Penicillins
R CH2 CONH CHCONH
R1 CONH
O
R1 CONH CHS
HNR2
COOH
CONH
N
S
R2COOH
CONH
ON
S CH3
CH3COOH
HN
S
COOH
CH3
CH3
Cephalosporins
Penicillamine
HOOC CNH2
HCCH3
SHCH3 HOOC C
NH2
HCCH3
SCH3
Cys
S
Protein
Protein
Lys
Protein
Lys
Captopril
N
COOH
CO
CHCH3
CH2 SHN
COOH
CO
CHCH3
CH2 S S Cys Protein
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ROLE OF IMMUNE SYSTEM IN INITIATING DRUG-INDUCED ALLERGIC REACTIONS
Drug Protein Conjugate Formed in a Cell
Secreted
Injured Cell
Immature Dendritic Cell
Ag Processing
Ag Presentation byMHC Class 1 and 2
CD8+
CD4+ CD4+CD8+
HSPs, INF-,TNF-, IL-1
Migrate to Lymph Nodes Immunization of T Cells
Migrate to Lymph NodesTolerization of T Cells
IL-10, PGE2,TGF-
Regulatory T CellsMigration to Periphery Block Drug Allergy
Migration to Periphery Drug Allergy
B Cell
IgG, IgE,IgA
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PATHWAYS OF IMMUNOPATHOLOGY
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DRUG-INDUCED LIVER DISEASE IS A MAJOR HEALTH PROBLEM
It is a major cause of acute liver failure and a major safety reason for:
• Stopping preclinical development of drugs
• Terminating clinical trials of drugs • Withdrawing drugs postmarketing
F. Ballet, J. Hepatol., 26 (Suppl. 2), 26 (1997)
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LIVER DISEASE IS CAUSED BY MANY COMMONLY USED CLASSES OF DRUGS
• Antihypertensives• Lipid-lowering
agents• NSAIDs• Antimicrobials• Antidiabetic agents
• Anticonvulsants• Psychotropic
agents• Inhalation
anesthetics• Herbal medicines
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DRUGS WITHDRAWN / NOT APPROVED DUE TO LIVER DISEASE
Iproniazid Ibufenac (Europe)Ticrynafen Benoxaprofen Perhexilene (France)Dilevalol (Portugal and Ireland)Bromfenac Troglitazone Nefazodone (Serzone)Ximelagatran (Exanta)
1956197519801982198519901998200020032004
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Initiation Progression Secondary Injury Repair
COMPLEXITY OF DRUG-INDUCED LIVER DISEASE
Reactive MetabolitesProtein AdductsROS, RNSInjury
Innate Immune System Activation
Dendritic Cells
Kupffer Cells
NK and NKT Cells, Monocytes, PMNs, and EosinophilsAdaptive Immune System Activation
Effector Abs and T Cells
Death
Release of Protein AdductsRelease of Adjuvants
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PATHWAY OF HALOTHANE-INDUCED ALLERGIC HEPATITIS
P 4 5 0
H e p a to c yte
H u m o ra l a n d C e llu la r Im m u n e R e s p o n s e s
H a lo th a n e T riflu o ro a c e ty l C h lo rid e
T o x ic ity
C
F
C
F
H
C l
B rF C
F
C
F
F C l
O C F
F
C
O F
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HALOTHANE HEPATITIS PATIENTS’ SERUM ANTIBODIES (% REACTIVITY)
Antigen TFA-Protein Native-Protein
PDI 10 5
PDI isoform 55 25
Carboxylesterase 13 5
Calreticulin 5 3
ERP72 30 25
GRP94 65 28
CYP2E1 45
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OTHER FLUORINATED INHALATION ANESTHETICS FORM IDENTICAL
PROTEIN ADDUCTS
H a lo th a n e
CF
C
F
H
C lB rF C
FO
FHCC
H
C lFF
FCF
OF
HCCH
FFF
F
Is o flu ra n e D e s flu ra n e
H e p a to c y te
C FF
CO F
P 4 5 0
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CYP AUTOANTIBODIES ASSOCIATED WITH OTHER DRUGS CAUSING ALLERGIC HEPATITIS
Drug
Tienilic acid
Dihydralazine
Ethanol
Antigen
CYP2C9
CYP1A2
CYP2E1, CYP3A4, CYP2E1-hydroxyethyl radical
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T CELL REACTIVITY ASSOCTIATED WITH DRUGS CAUSING ALLERGIC HEPATITIS
CotrimoxazoleErythromycinKetoconazoleAmpicillinAllopurinolIbuprofenCaptopril-MethyldopaEnalapril
Maria and Victorino, Gut, 41, 534 (1997)
ChlorpromazineAmineptineDothiepinePhenytoinCarbamazepineTamoxifenGlibenclamideLovastatinPropylthiouracil
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MECHANISM OF ACETAMINOPHEN (APAP) HEPATOTOXICITY
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SERUM CYTOKINE LEVELS AFTER APAP TREATMENT OF MICE
Time (hr)
4 8 12 240
3000
6000
9000
12000
15000ALT
IU/L
4 8 12 240
100
200
300IL-4
pg/m
L
4 8 12 240
100
200
300IL-10
pg/m
L
4 8 12 240
100
200
300
400
500IL-13
pg/m
L
IL-6
4 8 12 240
40
80
120
160
200
pg/m
L
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IL-10 DEFICIENCY INCREASES APAP-INDUCED LIVER INJURY AND DEATH
Time (hours)0 10 20 30 40 50
Surv
ival
(%)
0
20
40
60
80
100
Wild Type IL-10 KO
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APAP-LIVER NECROSIS IN IL-10-/- MOUSE
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IL-10 REGULATES iNOS L
iver
iNO
S m
RN
A L
evel
(Arb
itrar
y U
nit)
0.00
0.25
0.50
0.75
*
Wild-Type Knockout
Wild-Type Knockout
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IL-10/iNOS KO MICE ARE NO MORE SUSCEPTIBLE TO APAP THAN WT
MICE
A B C D0
1000
2000
3000
4000
5000
*A= Wild Type APAPB= IL-10 KO APAPC= iNOS/IL-10 KO APAPD= iNOS KO APAP
ALT
(IU
/L)
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• Diclofenac: G. P. Aithal et al., Gastroenterology, 118(4), 1077, Part 1, Supplement. 2. April 2000
• Ethanol: J. Grove et al., Gut 46, 540-545 (2000)
IL-10 PROMOTER POLYMORPHISMS IN DRUG-INDUCED LIVER DISEASE
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OTHER HEPATOPROTECTIVE FACTORS UNCOVERED WITH KNOCK OUT MICE
• IL-6: liver regeneration, prevents apoptosis, induces HSPs
• COX-2: prostaglandin products induce HSPs and prevent inflammation
• IL-4 and IL-13: mechanisms not yet defined• Nrf2: regulates induction of GSH synthesis,
UGTs, GSTs, NADPH quinone reductase, heme oxygenase, catalase
• CCR2: down regulates INF-γ and TNF-α
Y. Masubuchi K. Chan, et. al., PNAS, 98, 4611 (2001); C.M. Hogaboam, et. al., Am. J. Pathol., 156, 1245 (2000).
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NIH FUNDS NETWORK TO STUDY DRUG-INDUCED LIVER INJURY (DILIN)
• Sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2004
• The DILIN centers are located at U. of North Carolina, Duke, U. of Michigan, U. of Connecticut, and U. of California in SF
• The goal is to establish a registry of patients who have experienced severe drug-induced liver disease and collect biological samples for biochemical, serological, and genetic testing by investigators throughout the country
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DRUG-INDUCED CUTANEOUS ADRS
• Exanthems-95% are erythematous or maculo-papular in nature and are usually self-limiting when the drug is withdrawn, Steven-Johnson syndrome and toxic epidermal necrolysis are life-threatening
• Exanthems from β-lactam antibiotics are often mediated by drug-specific IgE antibodies while many others by CD4+ and CD8+ T cellsN. Yawalkar, Toxicology, 209, 131(2005)
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T CELL REACTIVITY TO DRUGS CAUSING CUTANEOUS ADRS
• Lidocaine• Sulfonamides -Lactam antibiotics • Phenytoin• CarbamazepineLebrec et al., Cell Biology and Toxicology, 15, 57 (1999)
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MACULO-PAPULAR EXANTHEM AND TOXIC EPIDERMAL NECROLYSIS
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MECHANISM OF T-CELL MEDIATED CUTANEOUS ADRS
S. Roychowdhury and. C.K. Svensson, The
AAPS Journal, 7, E834 (2005)
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MECHANISMS OF DRUG-INDUCED IMMUNE-MEDIATED BLOOD DYSCRASIAS
D rug
Anti-D rugAb
B ind and activa tecom p lem en t
B ind to Fc receptorof m acrop hages
Cell lys is
Im m uneC om plex
Lysis by com plem entan d /o r m acro phages
HAPT EN M EC HANISM
IM M UNE C O M P LEX M EC HANISM
AUT O ANT IB O DY M EC HANISM
AutoAbLysis by com p lem entand/or m acrophages
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DRUG-INDUCED IMMUNE-MEDIATED HEMOLYTIC ANEMIA
Hapten Mechanism
Immune Complex Mechanism
Autoantibody Mechanism
Ampicillin Diclofenac CephalosporinsCarbenicillin Isoniazid DiclofenacPenicillin Tetracycline LevodopaMethicillin Quinidine MethyldopaCephalosporin Thiopental ProcainamideTetracycline Chlorpromazine NomifensineTolbutamide Nomifensine TolmentinT. Deloughery, Immunol. Allergy Clin. of North Am. 18, 829 (1998)
Lists drugs causing aplastic anemia, agranulocytosis, and thrombocytopenia
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IgE-MEDIATED ANAPHYLACTIC DRUG REACTIONS
AlcuroniumCephalosporinsPenicillinsProtamineStreptokinase
Park et al., Chem. Res. Toxicol., 11, 969 (1998); B.Y.H. Thong and Y. Chan, Ann. Allergy Asthma
Immunol., 92, 619 (2004).
SulfamethoxazoleSuxamethoniumThiopentoneTrimethoprineTubocurarine
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MECHANISM OF DRUG-INDUCED ANAPHYLAXIS
IgE-secretingplasm a cell
M ast cell or basophil
Drug
1. Airway sm ooth m uscle contractionleading to bronchospasm2. Increase permeability of b lood vesselsand mucous g land secretion3. Inflam m ation (eosinophils andneutrophils)4 . Respiratory, gastro intestinal, cutaneous,and cardiovascular system s can be involved
Histam ine, leukotrienes, and cytokines
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ASSOCIATION OF GENETIC VARIANTS OF HLA-B AND HSP70 WITH HYPERSENTIVITY
TO ABACAVIR• Abacavir is a nucleoside reverse transcriptase inhibitor
used to treat HIV type 1• Approximately 5% of patients who receive abacavir develop
a treatment-limiting hypersensitivity reaction, characterized by fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea or pain) and lethargy or malaise
• Median time to onset is 11 days, but symptoms occur within hours when patients are rechallenged
• Susceptibility is associated with specific variants of HLA-B and HSP70 and CD8+ T cells that are activated in presence of abacavir to produce TNF
A.M. Martin, et. al., PNAS, 101, 4180 (2004)
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PSEUDOALLERGIC (ANAPHYLACTOID) REACTIONS WITH NSAIDS
• Most cases occur with aspirin, although other NSAIDs can be involved except for COX-2 inhibitors
• Reactions include asthma, rhinitis, urticaria and/or anaphylactic shock.
• Not mediated by IgE antibodies• COX-1 inhibitors may divert arachidonic
acid metabolism to 5-lipoxygenase pathways and formation of proinflam-matory cysteine-leukotrienes
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PSEUDOALLERGIC (ANAPHYLACTOID) REACTIONS WITH NSAIDS
• Leukotrienes cause bronchial smooth muscle contraction, mucous secretion, vasodilation, and cellular infiltration
• Cysteine-leukotriene receptor 2 poly-morphisms associated with aspirin intolerance
J.S. Park et al., Pharmacolgenics and Genomics, 15, 483 (2005)
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ANAPHYLACTOID REACTIONS WITH IODINATED RADIOCONTRAST AGENTS
• Reactions can be similar to aspirin and include asthma, rhinitis, urticaria, gastrointestinal symptoms, and/or anaphylactic shock consisting of hypotension, pulmonary edema, respiratory arrest, cardiac arrest, and convulsions
• Mechanisms?
J. Szebeni, Toxicology 216, 106 (2005)
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MECHANISMS OF REACTIONS TO RADIOCONTRAST REAGENTS
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ENZYME POLYMORPHISMS AND TYPE B ADVERSE DRUG REACTIONS
• Sensitivity to warfarin and phenytoin due to metabolic deficiency caused by CYP2C9*3Rettie et al., Epilepsy Research, 35, 253 (1999); Brandolese et al., Clin. Pharmacol. Ther., 70, 391 (2001)
• Irinotecan side effects of serious and potentially fatal diarrhea and neutropenia are associated with metabolic deficiency caused by UGT1A1*28 and other allelic forms of UGT1AHan et al., J. Clin. Oncol., 24, 2237 -2244 (2006)
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THIOPURINE-S-METHYLTRANSFERASE POLYMORPHISMS AND TYPE B ADR
• Thiopurine drugs 6-mercaptopurine and aza-thioprine are used to treat acute lymphoblastic leukemia in children, inflammatory bowel disease, autoimmune disease, and organ transplant recipients
• Polymorphisms of TPMT that lead to low enzyme activity result in life-threatening pancytopenia
L. Wang and R. Weinshilboum, Ongene, 25, 1629-1638 (2006)
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THIOPURINE METABOLISM RESULTS IN THERAPEUTIC ACTIVITY AND TOXICITY
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DRUG-INDUCED-LONG QT SYNDROME• Results in prolonged ventricle repolarization that can lead to
polymorphic ventricular tachycardia (torsade de pontes), and ultimately ventricular fibrillation and death
• Rare, unpredictable, and a major reason for withdrawal or restriction of many drugs
• Antiarrhythmic drugs such as quinidine, procainamide, sotalol and others
• Other classes of drugs cause this syndrome including astemizole (antihistamine), terfenadine (antihistamine), mibefradil (anti-hypertensive), and grepafloxacin (antibiotic)
• Linked to genetic variants of drug-metabolizing enzymes• Linked to cardiac K ion channel subclinical mutations
P.J. Kannankeril and D.M Roden, Current Opinion in Cardiology, 22, 39 (2007)
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Summary
• Drug-drug interactions are a major cause of Type A ADRs and are in many cases predictable
• Type B ADRs may be caused by rare allelic forms of enzymes, receptors, ion channels, transporters, transcription factors, etc
• Many Type B ADRs also appear to be mediated by specific Abs and T cells that are induced by protein adducts of reactive metabolites
• It is likely that numerous factors protect most people from getting Type B ADRs and rare polymorphisms of one or more of these factors determine individual susceptibility
• Toxicogenomics and proteomics should provide new information about other important regulatory factors that normally protect cells from TYPE B ADRs
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