Professional Documents
Culture Documents
Deni*ons
Pharmacogenomics:
Analysing
en*re
genomes,
across
groups
of
individuals,
to
iden*fy
the
gene*c
factors
inuencing
responses
to
a
drug.
Pharmacogene-cs:
Studying
an
individual's
gene*c
make
up
in
order
to
predict
responses
to
a
drug
and
guide
prescrip*on.
Objec*ves
of
Pharmacogene*cs
1. Iden*fy
varia*on
in
response
2. Elucidate
molecular
mechanisms
3.
Evaluate
clinical
signicance
4.
Develop
screening
tests
5.
Individualize
drug
therapy
Personalized Medicine!
Personalized Medicine!
Medicine is personal:!
We are all different.!
Some of our differences translate into how we react to drugs
as individuals.!
This is why personalized medicine is important to
everyone.!
Variability of Disease!
Variability of Disease!
What is DNA?
April
1953
Drs.
James
Watson
and
Francis
Crick
determined
the
structure
of
DNA
(double
helix)
April 1953
April 2003
What is Pharmacogenomics?
R
X
Pharmacogenomics?
Pharma = drug or medicine
Genomics = the study of genes
R
X
What
is
Pharmacogenomics?
Pharma = drug or medicine
Genomics = the study of genes
R
X
Tumoricide
30%
No Eect/Hurt
Helped
Tumoricide
No Eect/Hurt
Helped
Tumoricide
Why?
Your DNA
Your cells
A
Adenine
Adenine
Thymine
Adenine
Thymine
Cytosine
Adenine
Thymine
Cytosine
Guanine
Protein!
Met
Met
Val
Met
Val
Leu
Met
Val
Leu
Ser
Met
Val
Leu
Ser
Pro
Met
Val
Leu
Ser
Pro
DNA:
Met
Val
Leu
Ser
Pro
DNA:
Amino
Acids/Protein:
Met
Val
Leu
Ser
Pro
Met
Val
Leu
Ser
Thr
DNA:
Amino
Acids/Protein:
Met
Val
Leu
Ser
Pro
Met
Val
Leu
Ser
Thr
DNA:
Amino
Acids/Protein:
Words:
Met
Val
Leu
Ser
Pro
Met
Val
Leu
Ser
Thr
Amino
Acids/Protein:
Words:
Val
Leu
Ser
Pro
DNA:
Amino
Acids/Protein:
Words:
Met
Met
Val
Leu
Ser
Thr
No Eect/Hurt
Helped
Tumoricide
Cell
Cell
Cell
Receptor
(Protein)
Cell
Receptor
(Protein)
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Cell
Too
Few
(hyposensi-ve)
Cell
Cell
Cell
Cell
Cell
Too
Few
(hyposensi-ve)
Cell
Cell
Cell
Mutated
(insensitive)
Cell
Cell
PTC
Taste
cell
This
tastes
bi/er!
Phenylthiocarbamide
PTC
Taste
cell
This
tastes
bi/er!
PTC
Non-
binding
PTC-
Receptor
Taste
cell
I
dont
taste
anything!
TT
Tt
TT
Tt
TT
Tt
TT
Tt
TT
Tt
TT
SUPERTASTER
Tt
TT
SUPERTASTER
Tt
This
tastes
bi[er!
TASTER
TT
SUPERTASTER
Tt
This
tastes
bi[er!
TASTER
NON-TASTER
No Eect/Hurt
Helped
Tumoricide
Why?
Y
Her2-
Her2+
No Eect/Hurt
Helped
Tumoricide
Her2-
Her2+
Her2+
+
American Journal of Clinical Pathology. 2008;129(2):263-273
Tumoricide
= ?
+
American Journal of Clinical Pathology. 2008;129(2):263-273
Tumoricide
Breast
Cancer
1990
Surgery
Radia-on
Chemotherapy
(drugs)
2012
Surgery
Radia-on
Chemotherapy
Specialized
treatments
(for
certain
types
of
breast
cancer)
http://www.ucdmc.ucdavis.edu/welcome/features/20080709_cancer_sweeney/index.html
Y
Her2-
Her2+
Tumoricide
Does
Not
Work
Tumoricide
Works!
TT
SUPERTASTER
Tt
This
tastes
bi[er!
TASTER
NON-TASTER
Papillae
bumps
on
your
tongue
Papillae
bumps
on
your
tongue
Taste
buds
cells
are
found
on
the
papilla
Papillae
bumps
on
your
tongue
Taste
buds
cells
are
found
on
the
papilla
Papillae
bumps
on
your
tongue
Nerve
Cell
Transmits
signal
to
brain
Taste
buds
cells
are
found
on
the
papilla
Brain
Wow!
This
tastes
really
bi[er
Papillae
bumps
on
your
tongue
Nerve
Cell
Transmits
signal
to
brain
Taste
buds
cells
are
found
on
the
papilla
5 papillae
20 papillae
35 papillae
5 papillae
20 papillae
35 papillae
super-taster
taster
A Drugs Life
ADME
Absorp-on
Distribu-on
Metabolism
Excre-on
http://publications.nigms.nih.gov/medbydesign/chapter1.html
Metabolic enzymes
Enzymes
Metabolites
Drug
Liver
B
A
Why?
B
A
ADME of Nortriptyline
100mg
Nortriptyline
ADME of Nortriptyline
100mg
Nortriptyline
Adverse reaction
Nothing happensGets better
95mg
5mg
50mg
Metabolites
Drug
Liver
Poor
Metabolizer
95mg
Metabolites
Drug
Liver
Ultrarapid
Metabolizer
5mg
Metabolites
Drug
Liver
Intermediate
Metabolizer
50mg
Poor Metabolizer
Ultrarapid Metabolizer
Decrease Dose
Increase Dose
Or change drug
Today
One-size-fits-all drugs
Current drug development system develops
drugs for the average patient
No simple way to determine who will respond
well and who will respond poorly
One size does NOT fit all!
Whats the solution?
Today
One-size-fits-all drugs
Current drug development system develops
drugs for the average patient
No simple way to determine who will respond
well and who will respond poorly
One size does NOT fit all!
Whats the solution?
Pharmacogenomics (PGx)
Personalized Medicine
April, 2050
You wake up feeling terrible, and you know it's time to
see a doctor. In the office, the physician looks you over,
listens to your symptoms, and decides to prescribe you
a drug.
But first, the doctor takes a look at your DNA.
Summary
Gene-c
varia-on
leads
to
phenotypic
dierences
and
dierences
in
how
we
all
react
to
drugs.
Summary
Gene-c
varia-on
leads
to
phenotypic
dierences
and
dierences
in
how
we
all
react
to
drugs.
Summary
Gene-c
varia-on
leads
to
phenotypic
dierences
and
dierences
in
how
we
all
react
to
drugs.
Summary
Gene-c
varia-on
leads
to
phenotypic
dierences
and
dierences
in
how
we
all
react
to
drugs.
Pharamcogenomics
Using
peoples
gene-c
informa-on
for
the
right
drug
at
the
right
dose
at
the
right
-me!
R
X
Pharmacogenetics &
Pharmacogenomics!
Pharmacogenetics &
Pharmacogenomics"
http://www.pharmgkb.org/!
Pharmacogenetics: study of individual gene-drug
interactions, usually one or two genes that have
dominant effect on a drug response (SIMPLE
relationship)!
Pharmacogenomics: study of genomic influence on
drug response, often using high-throughput data
(sequencing, SNP chip, expression, proteomics COMPLEX interactions)!
PharmGKB Website:
http://www.pharmgkb.org/!
6-mercaptopurine!
6-thioguanine
azathioprine!
Metabolism of 6-MP!
Polymorphic!
Cytochrome!
P-450s!
Sconce et al. Blood 2005, Yuan et al. Human Mol Genetics 2005, Schelleman et al.
Clin Pharmacol Ther 2007, Montes et al Br J Haemat 2006!
"
!
23andMe!
Drug Response!
Reports!
Personalized Drugs!
Hercep*n
Erbitux
Tarceva
Straeera
6-MP
An*virals
Xie and Frueh, Pharmacogenomics steps toward Personalized Medicine, Personalized Medicine 2005, 2,
325-337!
http://ama.learn.com
154
Frequency
Normal Distribution
Activity
155
Polymorphic Distribution
GENETIC
POLYMORPHISMS
Pharmacokinetic
Transporters
Plasma protein binding
Metabolism
Pharmacodynamic
Receptors
Ion channels
Enzymes
Immune molecules
157
From: Evans
WE, Relling MV.
Pharmacogenom
ics: Translating
functional
genomics into
rational
therapeutics.
Science
286:487-491,
1999.
158
(H3C)3NH2CH2C O C CH2CH2
choline
+
C O CH2CH2N(CH3)3
succinylmonocholine
Hydrolysis by pseudocholinesterase
% Inhibition
Typical
Atypical
100
80
60
40
20
0
-6
-4
161
162
HMP Shunt
G-6-PD
Dependent
CYP
MPO
PGH Synthase
NADP+ or
GSSG(?)
NADPH
or GSH(?)
R-NOH
O2
R-NOH
HgbFe+2
R-NO
HgbFe+3
GSH
Semi-mercaptal
sulfinamide
R-NH2
ERYTHROCYTE
NAD+
MetHgb
Reductase
Reactive
Oxygen
NADH
Splenic
Sequestration
SOD
Catalase
GSH Peroxidase
Detoxification
Hemolytic
Anemia
163
Primaquine
Nalidixic Acid
Sulfapyridine
164
8
0.7-3
165
166
C. N-ACETYLTRANSFERASE ACTIVITY
NAT1*4
NAT2*4
PABA
PAS
SMX
PA
DDS
SMZ
AF
NAT2*5A
NAT2*6A
NAT2*7A
168
% Slow
% Hetero Fast
59
58.6
54.6
10.5
12
22
35.6
35.9
38.6
43.8
45.3
49.8
% Homo Fast
5.4
5.5
6.8
45.7
42.7
28.2
169
XENOBIOTICS SUBJECT TO
POLYMORPHIC ACETYLATION IN MAN
Hydrazines
Arylamines
isoniazid
dapsone
hydralazine
procainamide
phenylzine
sulfamethazine
acetylhydrazine
sulfapyridine
hydrazine
aminoglutethimide
Carcinogenic
Arylamines
benzidine
-naphthylamine
4-aminobiphenyl
ADVERSE EFFECTS TO
SULFASALAZINE IN PATIENTS WITH
INFLAMMATORY BOWEL DISEASE
SULFASALAZINE
H
N
COOH
O
S
N N
OH
COOH
H
N
O
S
O
SULFAPYRIDINE
NH2
H2 N
OH
5-AMINOSALICYLIC ACID
171
ADVERSE EFFECTS TO
SULFASALAZINE IN PATIENTS WITH
INFLAMMATORY BOWEL DISEASE
Frequency of side effect
Slow Acetylators Fast Acetylators
Side Effect
9
1
cyanosis
5
0
hemolysis
6
0
transient reticulocytosis
120
100
80
60
Slow Acetylators
40
Fast Acetylators
20
0
0
20
40
60
80
100
PROCAINAMIDE
O
(H3CH2C)2NH2CH2CHN
CYP450
NH2
NAT
O
(H3CH2C)2NH2CH2CHN
PROCAINAMIDE HYDROXYLAMINE
NHOH
(H3CH2C)2NH2CH2CHN
NH CCH3
N-ACETYLPROCAINAMIDE
174
Percentage of Subjects
100
Control
HS
80
60
40
20
0
SLOW
FAST
175
SMX-glucuronide
UDPGT
NH2
S
O
H
N
N
O
NAT1
CH3
N-acetyl-SMX
Sulfamethoxazole
(SMX)
CYP2C9
MPO
PGH SYNTHASE
Detox
Nitroso
SMX hydroxylamine
NAT1
O-acetylation
Covalent binding to
cellular macromolecules/
cytotoxicity
Hypersensitivity/
Adverse Reaction
Hydroxamic
acid
N,O-AT
Acetoxy ester
Detoxified metabolite
176
D. CYP2D6 ACTIVITY
OH
CYP2D6
N
C NH
C NH
NH2
NH2
4-HYDROXYDEBRISOQUINE
DEBRISOQUINE
N CH3
N CH3
CYP2D6
H
OH
OCH3
DEXTROMETHORPHAN
DEXTRORPHAN
177
178
bufuralol
encainide
guanoxan
paroxetine
propranolol
clomipramine
ethylmorphine
imipramine
phenformin
179
6-glucuronidation
H3CO
codeine-6-glucuronide
M-6-G
O
O-demethylation
CYP2D6
morphine
NCH3
M-3-G
normorphine
HO
CODEINE
N-demethylation
norcodeine
norcodeine6-glucuronide
182
20
EM
15
EM + Q
10
5
0
1 1.5 2 2.5
Time (hr)
EM
Pain
Threshold
(mA)
Morphine Conc
(nM)
10
8 EM + Q
6
4
2
0
0
1
Time (hr)
183
# of
Subjects
9
Metabolic
Ratio
0.33
CYP2D6wt/CYP2D6wt
12
1.50
CYP2D6wt/CYP2D6(A or B)
2.14
CYP2D6B/CYP2D6B
48.84
185
186
E. CYP2C9 ACTIVITY
Prescribed Daily Warfarin Dose and CYP2C9 Genotype
Warfarin Dose*
5.63 (2.56)
4.88 (2.57)
3.32 (0.94)
4.07 (1.48)
2.34 (0.35)
1.60 (0.81)
Genotype
*1/*1
*1/*2
*1/*3
*2/*2
*2/*3
*3/*3
6-methylmercaptopurine
SCH3
SH
N
TPMT
N
H
SAM
N
H
SAH
188
Frequency
TPMT Activity
Distribution of Thiopurine Methyl-transferase Activity.
Reproduced from: Weinshelboum RM, Sladek SL. Am J Hum Genet 32:651-662, 1980.
189
190
Weight Reduction
252 g
520 g
GST1 AA/Aa
GST1 aa
285 g
642 g
From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of
gliomas to alkylating agents. NEJM 243:1350-1354, 2000.
193
From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of
gliomas to alkylating agents. NEJM 243:1350-1354, 2000.
194
195
. G G T A A C T G
. G G C A A C T G ...
Predictive of efficacy
Predictive of no efficacy
197