Transcript exposure

Idiosyncratic reactions:
Individual factors
leading to response (adverse
reactions for instance)
upon exposure to a xenobiotic
Xenobiotic
Individual factors
response
Pharmaco- or toxicological
Xenobiotics = small M.W. foreign compounds
- drugs,
- atmospheric and alimentary compounds,
- pollutants as well as natural products
Exposure unavoidable
Influence of metabolism on xenobiotic response
Xenobiotic
XME
Metabolites A
Metabolites B
Target
Elimination
XME expression may vary according to
- genetic
factors
- environmental
pharmaco
toxico
Xenobiotic
Exposure
Metabolites
Elimination
No response
metabolism
Target:
interactions with
proteins (receptors
enzymes…), ADN, lipids,
small molecules
target
Defense system, immune system
Reaction
(cell, organ,
organism)
Pharmacological or
Toxicological response
Response
Gene
Medications
Response linked to polymorphism
Metabolism
CYP2C9
CYP2D6
Tolbutamide, warfarin, phenytoin,
nonsteroidal anti-inflammatories
Beta blockers, antidepressants, antipsychotics,
codeine, debrisoquin, dextromethorphan,
encainide, flecainide, guanoxan,
methoxyamphetamine, N-propylajmaline,
perhexiline, phenacetin, phenformin,
propafenone, sparteinedependence;
imipramine dose
Anticoagulant effect of warfarin
Tardive dyskinesia from antipsychotics
narcotic side effects, efficacy, and
requirement; beta-blocker effect
Dihydropyrimidine
dehydrogenase
Fluorouracil
Fluorouracil neurotoxicity
Thiopurine
methyltransferase
Mercaptopurine, thioguanine, azathioprine
Transport mdr1
digoxin, anti HIV
Thiopurine toxicity and efficacy; risk of
second cancers
plasma concentration, effect
Target
ACE
Enalapril, lisinopril, captopril
Renoprotective effects, cardiac indices,
blood pressure, immunoglobulin A
nephropathy
Quinidine
Cisapride
Drug-induced long QT syndrome
Drug-induced torsade de pointe
KvLQT
Terfenadine, disopyramide, meflaquine
Drug-induced long QT syndrome
hKCNE2
Clarithromycin
Drug-induced arrhythmia
Potassium channels
HERG
THIOPURINE METHYL-TRANSFERASE (TPMT)
AZATHIOPRINE METABOLISM
AZATHIOPRINE
GSTs
6-MERCAPTOPURINE
TPMT
HGPRT,
…
6-MMP
6-THIOGUANINE Ntides
6-TGN
TOXIC
ACTIVE
XO
THIOURIC
ACID
Xenobiotic
Exposure
Metabolites B
Elimination
No response
Target:
interactions with
proteins
(receptors
Interaction
with
cell, receptor
enzymes…), ADN, lipids,
small molecules
metabolism
target
Defense system, immune system
Reaction
(cell, organ,
organism)
Pharmacological or
Toxicological response
Response
Response to chemotherapy
in head and neck cancer
• 68% of the patients have an altered p53 in
the tumor.
• 87% of non responders and 57% of the
responders (p<0,003) have an alteration of
p53.
Response to chemotherapy
in head and neck cancer
Logistic regression
Variable
RR*
IC 95%
Stade
I+II
1
III
1,1
0,3-4
IV
1,4
0,5-3,7
p53 alteration
no
1
yes
4,9
1,5-15,6
*Relative risk of non response
Cabelguenne et coll.
Xenobiotic
Exposure
Metabolites B
Elimination
No response
Target:
interactions with
proteins
(receptors
Interaction
with
cell, receptor
enzymes…), ADN, lipids,
small molecules
metabolism
target
Defense system, immune system
Reaction
(cell, organ,
organism)
Pharmacological or
Toxicological response
Response
Examples of drugs inducing adverse immune reaction
Hepatitis
Tienilic acid
Dihydralazine
carbamazepine
anticonvulsants
Diclofenac
Halothane
Iproniazid
Agranulocytosis
sulfamides
Blood dyscrasias
Procainamide
aminopyrine
clozapine
carbamazepine
propylthiouracile
hydralazine
Systemic lupus erythromatosus
hydralazine
sulfamides
Toxidermias
sulfamides
anticonvulsants
penicillins
quinolones
anti-HIV
Clozapine
anti-HIV
quinolones
NSAIDs
anti-HIV
* These diseases are life-threatening
* They cannot be predicted
* which individuals?
* which drugs?
* Mechanisms? -----> prediction
* metabolism
* individual reaction
Xenobiotic: X
exposure
Metabolism
Reactive Metabolite: RM*
P-RM*
EMR*
Neoantigen
Presentation to the immune system
Immune
response
Toxic response
depends on many factors
variable
2nd exposure
control
H3C
NHSO2
O
NH2
N
NAT2
CYP 2C9
UGT
Detoxication
H3C
NHSO2
O
NHOH
N
GSH
H3C
NHSO2
O
from Park et al. 1998
N
N
O
Lyell syndrome, TEN:
very severe toxidermia to sulfamides
13/14 NAT2 -
Toxidermias in AIDS patients treated
with sulfamides
N
-
GSTM1 /
NAT2 (%)
46
(OR=2.5)
Patients
with Tx
41
Patients
without Tx
79
25
Total
130
32
Wolkenstein et al. 2000
Genotype/Phenotype discrepency
in AIDS patients
64 Patients
phenotype
slow
55
rapid
9
Genotype
30
34
25 discrepencies genotype fast/phenotype slow
checked by sequence
Disease may modify the phenotype
Response is dependent on target cells
GST P1 genotype:
GST P1*B are protected against toxidermias
(OR~9.5 p< 0,005
Wolkenstein et al.
Response is also dependent on immune response
* In the same study: CD8+ above median --> OR 5,7
p<0,0005), Wolkenstein et al.
* HLA A30B13Cw6 more frequent than in control
population (Oszkaya-Bayazit, J. AM. Acad. Dermatol. 2001)
Toxicity of sulfamides linked to
-Metabolism ± (NAT2/GST…)
- Organism response + (GSTP1…)
- Immune response ++ (CD8, HLA…)
- multistep
- each factor has influence
Xenobiotic: X
exposure
Metabolism
Reactive Metabolite: RM*
P-RM*
EMR*
Neoantigen
Presentation to the immune system
Immune response
Toxic response
depends on many factors
variable
2nd exposure
control
Autoantibodies against xenobiotic metabolizing enzymes
disease
xenobiotic
autoantibodies
hepatitis
agranulocytosis
tienilic acid
CYP2C9, LKM2
dihydralazine CYP1A2, LM
anticonvulsants
CYP?
halothane
CYP2E1
iproniazide
MAO B
?
CYP2D6, LKM1
?
UGT, LKM3
?
GST
clozapine
MPO
Addison or PGS
?
CYP 17, 21, Scc
CYP 1A2
CYP 2A6
4
DRUG
4
1 Enzyme: E
Immune response
autoantibodies
4
P
Reactive metabolite: R*
3
R*-P
2
neoantigen
R*-E
C
Ar
S
4
O
1
Immune response
autoantibodies
CYP 2C9
3
C
S
O
O
H 2O
Ar
2
Neoantigen: AT-CYP 2C9
Cl
tiénilic acid
Cl
HO
C
Ar
Hépatitis
S
O
OCH2COOH
C
S
anti LKM2
O
Ar
Covalent Binding with human liver microsomes
and yeasts expressing a single human P450
Tienilic acid
Human liver microsomes
control yeasts
1A1
1A2
2C8
2C9
2C18
2C19
2D6
3A4
pmol/min/nmolP450
98
0
77
41
8-10
340-380
45-42
41
6
0-0
SPECIFICITY of the COVALENT BINDING of TIENILIC ACID
on HUMAN LIVER MICROSOMES
P 450 2C
cpm/band
2000
1000
with NADPH
without NADPH
.
0
0
10
20
30
protein migration
40
50 # bands
xenobiotic
+
enzyme
enzyme
enzyme
xenobiotic
R*
R*
R*
R*
R*
R*
R*
enzyme
R*
Covalent binding
Links between the formation of a protein-adduct
and
an abnormal immune reponse
In most cases a reactive metabolite was
produced; it was able bind to protein(s)
(covalent binding).
Tienilic acid
Halothane
CHFC
Dihydralazine
Diclofenac
Carbamazepine
Sulfamide
procainamide
Clozapine
Phenytoin
Iproniazide
......
Hypothesis:
the quantity of reactive
metabolite is important
- high production of reactive metabolite
- concentration of RM on one target
-
dose
-
RM *
adverse drug reaction
adverse drug reaction
Hypothesis:
the quantity of reactive
metabolite is important
- high production of reactive metabolite
- concentration of RM on one target
-
dose
-
RM *
adverse drug reaction
adverse drug reaction
Captoril: lower doses -------> lower incidence
Halothane: high variability in the covalent binding
Isoflurane and enflurane:
lower covalent binding
lower incidence hepatitis
CHFC: ????
clozapine / olenzapine:
highest covalent binding = highest incidence agranulocytosis
anticonvulsants, sulfamides:
higher sensitivity in patients with higher production of RM*
Xenobiotic: X
exposure
Metabolism
Reactive Metabolite: RM*
P-RM*
EMR*
Neoantigen
Presentation to the immune system
Immune response
Toxic response
depends on many factors
variable
2nd exposure
control
Animals models
- difficult: many factors to control
- metabolism
- generation of hapten
- variable immune response
* genetic
*non genetic
* Lewis, Th1:
Dihydralazine p.o. : liver disease, inflammation,
no autoantibodies
Dihydralazine, hapten s.c.: liver disease, inflammation
no autoantibodies
* BN (HgCl2), Th2:
Dihydralazine, hapten s.c.: no liver disease, no inflammation
autoantibodies
Tienilic acid, hapten s.c.:
no liver disease, no inflamma
no autoantibodies
Animal model Conclusions
* No complete disease was observed
* Partial response
Th1: inflammation, liver disease
Th2: autoantibodies
* Autoantibodies: not pathogenic
* Control of immune system
* unknown factors such as infection
Xenobiotic: X
exposure
Metabolism
Reactive Metabolite: RM*
P-RM*
EMR*
Neoantigen
Presentation to the immune system
Immune response
Toxic response
depends on many factors
variable
2nd exposure
control
Xenobiotic
P
r
o
t
e
i
n
:
P
*
Mo
l ecu
l ar mimicry: P
Enzyme: P
Reactive
meta
b o
l ite
M*
Auto-Ab
NEOANTIGEN
P* or P-M *
Immune response:
presentation, processing, HLA
B ce
l l s, autoantib odies, epitopes
T ce
l l s, Th1/Th2
To
l erance
Rare diseases not very we
l l understood
not predicta
b le (xeno
b iotic, individua
l s)
Sch
Anti-HIV treatments lead to:
- high prevalence of adverse reactions
(Fellay et al. Lancer 2001)
- hyperlipidémia (SREBP1c, ABC Cassette)
- numerous drug interactions (metabolism)
- variation in response (metabolism and transport)
Abacavir (Mellal et al. Lancet 2002)
- 4 to 9% ADR
- linked to HLA57
Conclusions
Xenobiotic
Exposure
Metabolites B
Elimination
No response
Target:
interactions with
proteins
(receptors
Interaction
with
cell, receptor
enzymes…), ADN, lipids,
small molecules
metabolism
target
Defense system, immune system
Reaction
(cell, organ,
organism)
Pharmacological or
Toxicological response
Response
HLA-B*5701
Abacavir hypersensitivity
HLA-B*5701
Flucloxacillin DILI cholestasis
HLA-B*5801
Allopurinol SJS
HLA-B*1502
Carbamazepine SJS (Asian)
HLA-B*1502
Phenytoin SJS (Asian)
HLA-A*3101
Carbamazepine SJS (european)
HLA-DRB1*1501
HLA-B*3802
HLA-B*7301
HLA-DRB5*0201
Co-amoxiclav SJS
Sulfomethoxazole SJS
oxicams SJS
Clozapine neutropenia
Becquemont, Pharmacogenomics 2010
D
Apoptosis
APC
no signal 2
Helper
T cell
Tolerance
D-->R*-->R*P=
Necrosis
danger signal
APC
Mphages
NK cells
cells
signal 2
Helper
T cell
B and T cell mediated toxicity
Autoantibodies production
Autoreactive
B-cell
T-cell