DISTRIBUTION AND PREVALENCE

OF CYP2C19 POLYMORPHISM
THAT UNDERLIE PMs PHENOTYPE
IN INDONESIAN POPULATION

Introduction :

Pharmacogenetics is study of linkage between

individuals genetics and individuals ability to
response to drugs.
Individual variation in response to drugs is a
major problem in clinical practice and in drug
development.
Genetic variants determine individual drugs
response.
The most well-characterized genes affecting drug
response are the drug-metabolism genes, such as
CYP2C19

Genetic Background of Drug Metabolism

CYP2C19 is cytochrome P-450 subfamily

responsible for the metabolism of drugs such
as anticonvulsant (S)-mephenytoin,
omeprazole, certain barbiturates, diazepam,
propranolol, citalopram, proguanil &
imipramine.
By genetic polymorphism study, individuals
can be characterized phenotypically as
extensive metabolizers (EMs) and poor
metabolizers (PMs).

PHARMACEUTICAL SUBSTRATES OF
CYP2C19
Drug

Reference

Amitriptyline
Barbiturates
Chlorproguanil
Citalopram
Clomipramine
Diazepam
Imipramine
Mephenytoin
Omeprazole
Proguanil
Propranolol

Melstrom et al, 1988

Adedoyin et al, 1994
Wright et al, 1995
Sindrup et al, 1993
Nielsen et al, 1994
Bertillson et al, 1989
Haefeli, et al, 1990
de Morias et al, 1994
Anderson et al, 1992
Andersson et al, 1990
Ward et al, 1989

POLYGENIC DETERMINANTS OF DRUG EFFECTS

Drug Metabolism Genotypes

Drug Concentration (%)

100

m/m

80
60

wt/m

40

wt/wt

20
0
0

10

Time (hours)

15

20

25

Frequency and Distribution

The impact of genetic background to drug

prescriptions :
- medicine
- socio-economic

Frequency of PMs has been reported:

# 3-6 % in Caucasians and Africans
# 13-23 % in Asians
# 61 % in Vanuatu population (Akira et al.)

INTERETHNIC VARIATIONS OF
CYP2C19 GENOTYPE
Caucasian
100

African

90

Korea

80

China

70

Japan

60

Philippines

50

Vanuatu

40
30
20
10
0

hmEM

htEM

PM

Two possible hypothesis for high frequency of

PMs in Vanuatu population:

Selective pressure.
Xenobiotic & malaria endemic in this population
show deviation of Hardy-Weinberg equilibrium. Its
unlikely that selective pressure play important role.

Genetic drift from Austronesian-speaking population.

Migration of Austronesian-speaking population from
south-east Asia to Vanuatu islands with minimal
interaction with Vanuatu islanders.

Methods

CYP2C19 genotyping has been done by PCRRFLP methods.

To detect CYP2C19m1, exon 5 was amplified &
digested by SmaI. Exon 4 was amplified &
digested with BamHI, to detect CYP2C19m2.

The strategy (see next slide)

STRATEGY
Sma I
CYP2C19wt

Intron 4
5

EXON 5

109 bp

CYP2C19m1

Intron 4

Sma I Digestion
Intron 5

wt/wt wt/m1 m1/m1

321 bp
212 bp

212 bp

EXON 5

109 bp

Intron 5
3

321 bp

BamH I
CYP2C19wt

Intron 3
5

EXON 4
175 bp

CYP2C19m2

Intron 3

EXON 4
271 bp

BamH I Digestion

Intron 4
3
96 bp

Intron 4
3

wt/wt wt/m2 m2/m2

271 bp
175 bp
96 bp

result
M

321 bp
212 bp

Exon 5
1 : exon 5 uncut
2 & 3 : wt/wt
4 : m1/m1
5 : wt/m1

8
271 bp
175 bp

Exon 4
1 : exon 4 uncut
2,3,6,7,8 : wt/m2
4,5 : wt/wt

INTERETHNIC VARIATIONS OF
CYP2C19 GENOTYPE
Caucasian
African
China
Korea
Japan
Philippines
Indonesia
Vanuatu

100
90
80
70
60
50
40
30
20
10
0

hmEM

htEM

PM

INTERETHNIC VARIATIONS OF
CYP2C19 GENOTYPE in indonesian population

Melayu

70

Jawa-Jepara

60

Sunda

50

Dayak
Bugis

40

Kajang
30
20
10
0

hmEM

htEM

PM

CONCLUSION
Mutation which is happen in
Indonesian population is SouthEast Asian mutation.
Interethnic variation of CYP2C19 in
Indonesian population need further
exploration.

DRUG
Carosiprodol
Diazepam
R-Hexobarbital
Lansoprazole
S-Mephenytoin
R-Mephobarbital
Moclobemide
N-Desmethyldiazepam
Omeprazole
(+) Pantoprazole
(+) Citalopram
Clomipramine
Imipramine
Proguanil
Propranolol
Alprazolam
Clozapine
Desmethylimipramine
Diphenylhydantoin
Fluvoxamine
Glibenclamide
Losartan
Meprobamate
Nicergoline
Triazolam
R-Warfarin

CYP2C19 PATH WA Y
N-demethylation
N-demethylation
3'hydroxilation
- hydroxilation
4' - hydroxilation
4' - hydroxilation
C- hydroxilation
3' - hydroxilation
5 - hydroxilation
O-demethylation
N-demethylation
N-demethylation
N-demethylation
cycloguanil formation
side chain oxidation
unknown
unknown
unknown
R- - hydroxy
unknown
unknown
unknown
unknown
unknown
unknown
7 - hydroxilation

%ORAL CLEARANCE10 0 *(em-PM )/ em

84% decline
56% decline
95% decline
85% decline
99% decline
98% decline (estimate)
63% decline
55% decline
86% decline
84% decline
43% decline
33% decline
42% decline
40% decline
25% decline
13% decline
0% decline
0% decline
14% decline
11% decline
0% decline
0% decline
0% decline
0% decline
6% decline
<10% decline