Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity

Abstract

Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP).
To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity.
Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation.
Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types.
Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.

Full text

:NTJ TUBERC LUNG D:54(3):256-261
◎2000:UATLD
Siow Ⅳ
"acetyitransferase 2 genotype affects the incidence
of isoniazid and rifampicin‐
induced hepatotoxicity
M.Ohnof十
:.Yamaguchi′
+1.Yamamoto′ ■
■Fukudar S.Yokota′
十
R.Maekura′
十
M.:tOri Y Yamamoto′
=
■ogura′
十
K.Maeda′
§
K.KomutarS I igarashi′
5J.Azuma'
★
Department of c‖
nica:Evaluation of Medicines and Therapeutics,Graduate School of Pharmaceutica:Sciences,
Osaka Universityr Departments of十
1nterna:Medicine and lCiinica!Laboratoryr Toneyama National Hospital′
and 5Second Department ofinternal Medicine,NIT West Osaka Hospital,OsakarJapan
SUMMARY
SETTING: JapanCSe in―
PatiCnts with pullmOnary tubc←
cu10sis and normal livcr functiOn rccciving trcatincnt
with isoniazid and rifampicin(INH+RMP)。
OBJECTiVE: To clucidatc thc rclatiOnship bctwccn N‐
acetyltransfcrase 2(NAT2)gcnotypc and thc incidcncc
Of isOniazid+rifampicin―
induccd hcpatOtOxicity.
DES:GN: Prospcctivc study. Aftcr
ヽ4T2* genOtyping,
77 paticnts were classincd into thrcc groups according tO
thcir NAT2)l gcnotypes: rapid―
typc(a hOmOzygotc of
ハ
こ4T2+4),intermediatc‐
type(a heterozygotc of NrAT2*4
and mutant anclcs)and slow―
typc(a COmbination of
mutant allclcs).Thcir biOchemical pronlcs ofl市
cr func‐
tiOn tcst werc invcstigatcd for 3 mOnths to asscss the
dcveloPment Of Serunl aminotransfcrasc clcvatiOn.
RESULT: Of the 77 Patients, 18.2%devclopcd advcrsc
hepatic rcactiOn within thc Arst mOnth of INH+RMP
trcatincnt.
ノヽ
signincant assOciation was Observed be―
twccn hcpatOtOxicity and N4T2* gcnotypc: comparcd
with rapid―
typc,thc rclativc risk was 4.0(95%C11.94-
6.06)for intcrmcdiate―
typc and 28.0(959る
C126.0-30.0)
for s10w_typc.EspcciaHy in s10M/typc,thc incidcnce Of
hcPatOtOxicity and scrum anlinotransfcrasc clcvatiOn
was signincantly highcr than in thc Othcr twO typcs.
CONCLuS:ON: Slow rも
4T2■
genOtypc signincantly af‐
fcctcd thc dcvc10pmcnt OfINH+RMP―
induced hcpato‐
10xicity.This suggcsts thc pOssibility thatハ
↓4T2■ gcno―
typing priOr tO mcdicatiOn may bc uscful in cvaluating
paticnts with high risk fOr INH+RⅣ
IP‐
induced hcpato‐
tOxlCity.
KEY WORDS: N―
acctyltransfcrasc 2(NAT2);gcnOtypc;
isoniazid;rifampicin;hcpatOtOxiCity
珈lTH THE INCREASING incidcncc Oftuberculosis
worldwidc,a grcatcr number of patients are cxposcd
to the risks Of a potentially serious hepatotoxiC Cffcct
by antitubcrculosis drugs.The cvaluation of paticnts
with a risk fOr isOniazid and rifampicin{INH+RNIP)
induced hepatOtOxicity is clinicaHv important in cur―
rent antitubcrculosis treatincnt.HcpatotoxiCity occurs
、vith greatcr frcquency in paticnts rcceiving both iso―
niazid and rifampicin than in thOse receiving isoniazid
alonc.l A drug―
drug intcraction、 vith hepatic enzymc
inductiOn by rifampicin has bccn suspcctcd as a causc
of this adverse evcnt.2,3
N―acetyitransferasc 2(NAT2)is mainly rcsponsi―
ble for isoniazid metabolism.The climinatiOn ratc of
isoniazid is triinodally distributcd in accordancc、
vith
thc phcnotypc/gcnOtypc of NAT2.4.5 The gcnetic
polymOrphism can bc a IIlatter of greatirnportancc in
mOdi″ing thc to対
c cffects Of antitubcrculosis drug
thcrapy.AlthOugh thc acctylator status ofthc individ―
ual has been suspectcd as a potent risk factOr for
isOniazid―
induced hcpatOtOxicity, considcrablc con―
trovcrsy still cxists amOng prcvious studies.2、
36-101n
aH Of these studics,acetylatOr status was detcrrllined
by NAT2 phenotyping in terms ofa bimOdal distribu―
tion n10dcl.No one has ever adopted a trilnOdal dis‐
tribution lnOdel to look intO the issuc above,Sincc thc
isoniazid acetylator phenotypc rcflccts the gcnotype
in paticnts、
vith uncOmplicatcd pullnOnary tubercilo―
sis,5 applying NAT2+gcnOtypincation may clucidatc
this cOntrovcrsial issuc.If a link bctween the fゞ
AT2).
genOWpe and the development OfINH+RMP―
induccd
hcpatOtOxicity can bc llladc clcaら
NAT2).genotyping
rllight rnake it pOssible tO evaluatc paticnts susceptible
to advcrsc hcpatic reactions priOr to adlninistration.
Thc prescnt study was invcstigated prospcctivcly to
Clan■
thC rcladon bctwcen the NAT2オ
gcnotypc and
the incidence of hcpatotoxicity in JapaneSe patients
suffcring from pullnonary tubcrcu10sis、
vhO had nOr
mal livcr function bcfOre colllnlencing inultidrug anti―
tubcrculosis trcatlllent、
vith isOniazid and rifampicin.
Corrcspondence to:JuniChi Azuma,MD,Dcpartmcnt of Clinical Evaluaion Of NIcdicincs and Thcrapcutた
s,Graduatc
School of Pharmaccutical Scicnccs,Osaka Univcrsity,1-6 Yainada―
oka,Suita,Osaka 5650871,Japan Tcl:(+81)6-6879-
8258.Fax:(+81)6-6879-8259.c― mail:azulua@phs.osaka―
u ac,p
A″′′ι′′s″ι777″
′ι″16 Aρ″′′1999.Fノ
77α
′Zlι
rsノ
ο
″′ιιθ
ρ
′
`ど
180ι
′οι
θ
″
1999

聖
d:NH+RMP―
induced hepatotoxdty 257
STUDY POPULAT:ON AND METHODS
Palyents
聾
惚
鰭
∬
出
穐
彗
躍
五
鸞
率
giblc fOr this prOspcctivc invcstigatiOn during 1996-
1998.
haJl:正
1町
lf」
踏
:1鳳
11:脚
島ξl掌
il:官
HBsAg and anti_HCミ
＼
b.At thc bcginning of treat―
椰l露
憔
i警
選
縦
醤
郡
::∬
lキ
き
稿
.(ぶ
ねf:lcttL:路
尋
翡
ilX:::
樹
撒
島
籍
島
榔
撥
「
drttdiltlf:li:inl。
°
撫ti::::1贅
l罐
電
pTょ
:
鴛
胤
cmtttcilttb者
諄
槻
艦
t肥
躍
COllllnlttees.
Dere″
η
ln∂
tlon of ace1/1alor stalυ
s∂
ccorC/1rDg
`0あ
りe NAT2'genolype
Total gcnOmic DNA was prcpared from patients'
pcripheral lymphOcytcs.For thc idcntincation of the
threc NAT2オ
mutations;481C tO T(NAT2オ
∫
),590G
lo A(NAT2オ
6)and 857G tO A(NAT2・
7),1l poly
欝
1潟
rttli窓
畷
I謂
騨
繋
np翼
鏑
締
ti
modincation Of the mcthOd Of Ncugcbaucr et al.12
RcactiOns、
vcrc carried out in a v01ume of 50
μ
lthat
contained 300 ng of genOrnic DNA,200
μ
M each Of
dNTR 100 nル
I each Of fOrward primcr(5′
‐
AGAT
GTGGCAGCCTCЪ
ヽ
GAA-3′
)and reverse primcr
(5′
―
ATTAGTGAGTTGGGTGttAC 34),10m市
l Tl・
ls
HCl(pH 8.3),1.5 mM MgC12,and 2.5 U AmpliTaq
陶
:盤
ぜ
・
受
写
謂
猟
ま
出
]1■
irT
56°
C,and l min at 72°
C)were cOnducted and wcrc
fOHO、
vcd by a inalcxtcnsion pcriod ofフ
lllin at 72°
C.
FO110wing PCR,a9μ
l aliquOt Of PCR―
product was
completely digcstcd with Kρ
″
I,■
79r and B′
777Hf.
The restrictiOn digcsts、
verc clcctrOphOrcsed on_h‐
,6
polyacrylalllide gel.
ゎ
肥
珊
lttL燒
緊
￨:ヨ
占
尊
:IttT∬
:
gotc of RAT2オ
4),an intcrmcdiate acetylator geno―
type(IA―
typc:a heterOzygote of NAT2オ
4 and mutant
allcles)and a s10、
v acetylatOr genotype(SA―
type: a
combinatiOn Of mutant allcles).4,S、
13●
5 As Only fOur al¨
lcles(NAT2・
4,オ
5B, '6A and丼
ア3)havC been rc―
ported tO date in Japancse subiects,13,14 identincation
ofthese threc mutatiOns is suficient tO dcAne alrlnOst all
ハ
ι4T2丼
allelesin a hOmogeneousJapanCSC populatiOn.15
ハ
ssessmenょ
Of drυg―
′
ρσ
υced serυ
m
a17n,ρ
οtransFer∂
se e′
ey∂
`′
on
m鷲
青耳
』I][1嵩
婁
:路
遮
f::器
ギ
盤∫
induccd hepatOtOxicity.Scrum AST and′
へLT cOncen―
1撥
I轟
越
1部
態
職
Юttilm青
霊
よrtttwttT鰐
憮
nlorc than twice the lcvcl bcfOrc adnlinistration and
田
『
」
二
:∬ l猟
よi:胤
ittitttr=冨
淵 I
torics is 3 1 1U/1fOr AST and 34 1U/1for ALI
Sね l15″
c∂
′an∂
1/sな
薔
ittI電
響
辮
掛
繊
:'」
ilil∫
i;￨liよ
『
ll:lii:Ji[複
l1lliti[L
wcre mcasurcd atthc bcginning OfINH+RMP treat―
mcnt.FOr pcak valucs,the highcst AST and ALT Icv_
inFttls古
颯
lttt鷺
∬
[∬
出
鵠
畿∬
cnccs in serum anlinotransfcrasc elcvatiOn bctwecn
ニ
ト
盲
i犠
i‖
:Jill椰
」
〔
『
]:1鷲
1
werc twO―
sidcd,and P<o.o5was choscn as lcvc1 0f
signincancc.Analysis was performcd with statVicw
Softwarc(vcrsiOn J4.02;Abacus COncepts,Inc.)and
Excc1 5.0(市
IiCrOsOft).
RESULTS
AccOrding to thc genctic analysis rcsults,amOng thc
鷲
蔦
犠
鱗
淋
葬
幣
:輝
、vas no signincant diffcrencc bctwccn the thrcc
groups、
vith rcgard tO agc,、
veight and sex distribu―
tion(48±
20 ycars,52.2■
12.2 kgin RA‐
typc;54±
account the tOtal numbcrs Of NAT2オ
4 and mutant
驚
異 濃
fi結
よ
ぶ ξ
::こ
驚
χ理
1艦
聡 駆 霧
1,
allclc hOmOzy30tC,46.4%vs 47.4%;NAT2・
4 allcle
and mutant a‖
clc hctcrOzygOtc, 44.8% vs 42.998;
mutant anelc homozygote, 8.898 vs 9.ア
ッ8. This
proves that Our sirllplified genOtypiflcatiOn mcthOd
a110、vs fairly accuratc idcntincation of genotypcs in a

258 The international JOurnal of Tuber(ulosis and Lung Disease
駆lllol秘
訛:lriぷ
〃l:::認
im力
pane賛
Genotype
Hea th
SutteCtS
η
`%ノ
Pat ents
o(%)
Acety ator
status
Total
(n=77)
RA―
type
(n=28)
IA―
type
(n=42)
SA―
type
(n= 7)
ハ
yハ
「
2★ 4/★
4
NA「
2'4/★
5
NA「
2☆ 4/☆
6
ハ
′4ア2★ イ
/★ 7
NA72★
ヌ
・
5
ハノ
ハ
「
2★ 夕
★
6
ハ
yハ
T2★
ヌ
★
ァ
ハ
メ72★
6/★ 6
ハJハ
″
☆
α
★
ア
ハル4″
☆
フ
7★ 7
lotal
90(464)
5(26)
61(314)
21(lo 8)
0(00)
2(10)
0(00)
5(26)
9(47)
1(05)
194(100)
28(364)
2(26)
31(402)
9(117)
0(00)
1(13)
0(00)
2(26)
3(29)
1(13)
77(100)
RA‐
type
lA―
type
SA type
40 60
incidence(%)
100
RA=rap d acetプ
atO●
A=intermed ate acety atoc sA=Jow acety atOr
hOmOgeneous Japanesc populatiOn.Thc distributiOns
Serunl anlinotransferase levels elevatcd abOvc thc
II:γ
;i」
:liよ
1鶯
li11lI:場
Ii祖
:lttl11(ffi【
∬
ピ
:T「
IL幌
『
:TI:倶
覺
撻IllttI彎
ミitt黒
:
fcrase,which nOrmaliscd withOut lnOdincation Ofthe
rcgimcn.Ofthc 42 1A―
typc paticnts,six(14.3%l cx―
pressed serurll anlinotransfcrasc clcvatiOn,with lcvcls
簿
翻:耐
電f蹴
lギ
露
il∬
fl露
∬
麟
11恭
「
tubcrcu10sis drugs fOr 2-4 wccks.GrOss anlinotrans―
醐
彗
憮
鷲
蕗
榊
篤
tぷ
lrttt青
蹴
筆
軋
1牌
ilt麗
よ
u∫
留nF
transfcrase clcvatiOn:the dOsc fOr patients、
vith hc―
thcir Own dOctOrs.
・
Figure l shO、
vs thc rclatiOnship bctwccn thc
どllilTWS緊
翼 鷲
w繁
:緊
尭
鷲 覧
rcmarkably signiicant differcnces as regards thc frc―
qucncy of serum anlinotransfcrase clcvatiOn during
trcatmcnt when cOmparing RA―
typc with SA―
type
aminOtransfcrascs are shown in Table 2 A and B.The
:::肌
二Ff∬
:お
;∬
』
::ilTや
温1精
無1
months Of trcatmcnt in cOmparisOn with thc Other
two types(P<0.05).
DiSCUSSioN
凛t::f篭
∫L手
ぅ
lyglj葛
螺
:til:i選
瀾:よ
讐
蝋ri漁
留
xl趣
観
穣
￨:Itrl彗
響
冨
lilllili1111:lil卦
[111姿
Iil:III:
clcvatiOn in spitc Of nOrinallivcr functiOn beforc mcd_
icatiOn.Thc clcvatiOn Of bOth AST and ALT in SA―
WttlC:F胤
蹴 lt糧
操
場
まlt視
∫
鵠
驚
llttTtittlcl踏
i脱
∬:飛
譜
鯖L:F
ま
‰
:l:鷺
鴛
tr蹴
富
l:1順
lltt∬
ir

+RMP―
induced hepatotoxicity
Table 2 Effects Of lNH+RINIP treatment on serlJm amlnOtransferases A va ues expressed as mean■
sD
A
AST(U4)
Acetylator status
R∧
―
type(η
=28)
IA type(ρ
=42)
SA type(η
=7)
3
176±
45
206=45
181■
46
235■ 90★
(η
=27)
293■
330★
(ρ
=40)
520■ 118★
￨
217■
72夫
303=229☆
481=212★
￨
209=66★
287■
197☆
471■
288☆
i
ALT(IU4)
12、ぃ′
eeks
203■
87
257■
145★
341■
85★
'
261
■
97★
372■
358☆
631■ 199★
￨
RA―
type(7‐
=28) 124±
65 222■
127 209■
112★
(n=27)
IA―
type(η
=42) 157■
55 207±
156★
259■ 164★
(η
=40)
SA type(ρ
=7) 164■
78 483=205★
+ 590■
426★
+
203
239
603
93・
177★
436☆
+
186=124 259±
143去
200■
141★
307± 210★
361■
,66☆
' 676■
411☆
Acety ator status was determ ned accord ng tO NAT2★
genotyp ng as n Tc.bel
・
ρ
<0 05 versus basa
iρ
く
0 05 versus RA type and iA‐
type
AST=aspartate am notransferase,Peak=the h 9heSt eve w th n the irst 3 mo∩
ths of cOmmenc ng treatment RA=rap d acety atori lA=ntermed ate
aCetブ
atO●
sA=s Ow acetyぬ
to嘔 ALT=a an ne am notransferase
typc group,an increasc in scrunl alllinotransfcrase Of
morc than thrce tirllcs the upper lilllit Of nOrmal、
vas
recorded in half of the IA―
typc patients、
vith hcpato―
toxic reactiOns.Thc IA typc group sccms likcly to
nccd c10scr attention than RA―
typc paticnts.Further
study is nccessary tO cOnf■
rm the signincancc ofrisk in
IA―
typc.
The critcria chOscn in this study resultcd in a
higher incidcncc Of INH+RⅣ
IP― induced hepatOtOx―
icity than in previous studics.11'AlthOugh these critc―
ria may bc lo、
v fOr deining clinically evident hcpati―
tis, wc bclievc that thcy are clinicaly uscful fOr
finding advcrse hepatic reactions carlicr and fOr prc―
venting the dcve10pmcnt Of Overt hepatitis.MOst Of
thc paticntsin this study who devclopcd scrunl anlino―
transfcrasc elcvatiOn Oflcvels higher than thc criteria,
nccdcd inodincation of thcir antitubcrcu10sis regilllcn
until thcir hepatic rcactiOn ccascd,and avoidcd overt
hcpatitis、
vith bilirubin elevation.ヽ
Ve rccently expcri
cnccd an instance in
、
vhich a patient
、vith SA―
type
gcne devc10pcd rcmarkablc anlinOtransfcrase eleva―
tions,with AST>700 and ALT>300,8 days after
starting a regimcn cOntaining isOniazid(7.5mノ
kノ
day)and rifampicin.Wc presumc that such seriOus
hepatic rcactiOns inay bc avoidablc if isoniazid dOs―
agc is Optirniscd frOl■
l thc initial regilllen according tO
Nノ4T2丼
genOtype.
Thc acctylatiOn capacity of thc individual patient
strongly inlucnccs the rnetabolisll1 0fisOniazid.IInpair―
mcnt of NAT2 activity and cnzyme inductiOn by
rifampicin likcly shift it fl・
Om thc maior pathways to
altcrnat市
c pathways which brm tOxic mctabolites
(Figure 2).Active radicals derivcd frOrll acctvlhvdra―
zine｀
・
1ド
、
1'。
r hydrazine2 haVe been incrilninatcd as a
possible cause of isOniazid_relatcd hepatOtOxicity in
t、vo hypotheses.
Ⅳ
litchen ct al.5、
18、 19 advanccd a
hypOthesis that isOniazid cOmpctcd、
vith acctylhydra―
雛
塁
∬
毬Fl:li麒
耳
:l:f::t常
鷺
∬:∬∫触
tO fOrm active radicals in s10、
v acetylatOrs,22
、
vhilc
JennCr and Ellard shOwcd that prctreatmcnt with
rifampicin did nOt increase the metabOlism by nOn―
acetylation rOutes Of acetylhydrazine in in vivO
human experilllents.23 on the Othcr hand,Sarma et
al.3 proposcd anothcr hypothcsis that daily adnlinis―
tration of rifampicin incrcased thc dircct cOnvcrslon24
0f isOniazid tO isOnicOtinic acid and hcpatOtOxic
hydrazinc in s10w acctylators.The plasma lcve1 0f
hydrazine has bcen shO、
vn to bc highcr in s10、
v than
in rapid acctylatOrs due tO cOmpetitive acctylatiOn
and thc synergistic effect Of rifampicin.25,26 The latter
hypOthesis strOngly supports our ObscrvatiOn that
プ
墜
一
〇
6N祠
歯
SOn aZ C
NHCOCH3
NH2
Acetylhydrazine
NAT21
NHCOCH3
NHCOCH3
Diacetylhydrazine
Figure 2
isonicotinyl
glycine
NH2
NH2
ヽ4etabolic path、
へ
/ays of i50niaZld
Hydrazine

The lnternatiOna!JOurna1 0f Tuberculosis and
IIIIl選
為
X:t籠
1:」
ype padens du五
ng com_
盛I犠
神
[『
鮮
壺:酪
}掘
営
have failcd tO rcach this cOnclusion.3,5,10 The fO110w_
ing reasons cOuld cxPlain thc discrepancy bctwcen
駆
事
榊
犠
鮮
「
質
::膜
Ill百
農
惧:轟i:l,I患
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∬
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ll:露
e■
轟
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:L:ifttξ
∬竃
認1遠
irnPIy that safcr and mOrc suitable doscs Of isOniazid
乱
れ1尉
Ⅷ手
:1後
志
賭
ttl:￡
it貯
胤cfttC
Thc substantial racial diffcrenccs in distributiOn Of
theハ
」
/4T2' gcnOtypc rcflect thc differcnccs in stan―
L轟
孟
惧F富
躍
。
慧
ふ
:λ
」
i:i∫
Ⅷ
RF黛
1:織
i評
」:i靴
1:ふ
雹
『
首
緊i;:::壁
arc no、
v invcstigating thc rclatiOn bct、
vccn accumula―
tion Of tOxic mctab01itcs and INH tt RMP_induccd
hcpatOtOxicity.
DiscOntinuatiOn of antitubcrcu10sis trcatincnt due
to hcpatOtOxic rcactiOn and insul‐
ncient doscs Of isO―
椰
鳥
罹
鱗
驀￨#狙
II「
∫
鮮
:lttλ
ttTttλ
tti詰
:譜
よ
rtl胤
lhCC°
m_
スc々 η
o14/1ettemenお
This studyヽ
vas suppOrtcd in Part by thc Nakatomi FoundatiOn
ReFerences
ll=iIよ
ilttili理
澪撃
〔lliyttll;;i];;浅
出;}
3ヽlitchcll J R,ThOrgcirssOn U R Blackヽ
/1,ct al.Incrcased inci
譜
H糧
∬
彙
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ぽt鳳
=1』
I:1器
欄
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毅
4 Dcguchi■
MashimO M,suzuki■
cOrrcla10n bctwecn acetv―
鮮
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lttc:i撃
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lw
12757-12760
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6 YamamotO■
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Thc structurc and charactcislcs
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:
mun 19931 191:811-816.
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L:TI肥
盤雪l
human populatiOns.Pharnnacogcnctics 1 9951 5:S56-S59′
16 0kumtira K,Kita■
Chikazawa S,Komada R Iwakawa s,Tan

NAr2'9enotype and iNH+RMP‐
induced hepatOtoxicity
261
器ilよ
∫
r露
」
‖l驚
『
留ittiγ
ざ
lr;l鳳
期
Thcr 1997:61:509-517
r謝
富
島
胤
RttI諸
出
よ
鰍l器
∬
ぼ
18 MitchcliJ R,Zimlllcrman H J,IShak K G,ct al lsOliazid livcr
翼‖
ふf糧
1諾
器
を
l:11:iIず
pЮ
baЫ
C pahOrn←
h驚
:波
ξ
式
ぶ】:I議
Ⅳ
lil泄
覧
‖
1牌
1ょ
22:111:甘
lttlilil[質
I[1lillj∬
lillil懸
1
col Thcr 19851 38:566-571
%澪
薔
』1誹
貯
驚
Ⅷ
:Pl蹴
I彗
粘
1蹴
紺
271111illilIIlifiil:)ililJI[書
ftti
RESUME
膜
:lil鳶
:露
:盤
:庶
ぬl露
:ギ1::∬
:iょ
l:1ぶ
iま
蓄
:Tt dC HS°
maJde∝
dc L」
amメ
dncぼ
NH+
邊
Iま
灘
I鱗
驚
1乱
胤」
認:儀
)
RESULTATS:Sur l'enscmblc,18,2%ont d`velopp`unc
r6actiOn sccOndairc h`patique au cOurs du prcmicr inOis
du traitcmcntINH tt RMP.on a Obscrv6 une assOcia―
tiOn significativc cntrc l'apparitiOn d'une h`patotOxicit6
ct lc g6nOtypcハ
↓4T2* :par cOmparaison avec le typc
rapide, lc risque rclatif fut dc 4,0(Ic95°
/。 1,94-6,06)
pour lc typc intcrm6diairc et dc 28,0(IC950/。
26,0-
30,0)pour lc typc lent.L'incidcncc dc l'h6patOtOxicit6 ct
dc l'616vatiOn des anlinOtransf6rases s`riques fut signifi_
cativcment plus`lcv`c,PartiCuliさ
rcmcnt danslc type lcnt
par cOmparaisOn aux dcux autres types,
CONCLUSioN:Un g`nOtypc lent NAT2■
innucncc dc
maniさ
rc significativc le d`ve10ppemcnt d'une h`patOtO_
xicit`induitc parINH tt Rル
IP,ccci suggさ
rc qu'un g6nO―
typagc dc NAT2オ
pr6alablc au traitemcnt pourrait etrc
utilc pour d`pistcr lcs paticnts a risquc`lev6 d'h6patO_
toxicit6 induitc par INH+RMP.
RESUMEN
聯
稚
驚i椰
鮮
]鯖
鮮
]I:1:黒
￨llllili｀
F五
;ITill留
∬iCi3fttTl::a∬
:
距
剛
壌
ilr鵠
賓
茅
露
:h暦
凛
lntani麗
::
cn trcs grupOs dc acucrdO cOn su gcnotipo AIAT2■
:un
椰聾
整
驚
麟Iぷ
1棋
invcstigarOn 10s perfilcs biOquFlllicOs dc la funci6n he‐
pitica durantc 3 mcscs Para cValuar el dcsarroHO de la
clcvaci6n dc la anlinotransfcrasa s6rica.
RESULTADOS:Del tOtal, 18,2% dcsarrOnaron reac‐
cioncs hepiticas advcrsas cn cl Prinlcr incs dc tratanlientO
con isOniacida―
rifampicina. sc obscⅣ
6 una asociaci6n
凛瓶
里11:温
撚
lcl■
:`猟
篇
∬
訂
需:胤
:宕
胤
な
:酬
常
虚
乳
蹴
菫
滉
胤
tttI量
:
憲l属
lЪ
f盤
留
晨:織
i:li獄
課
1驚
T江
∈