Update:July/1/1999
EHBR (Eisai Hyperbilirubinuria Rat or
Eisai Hyperbilirubinemic Rat)
執筆者:中根良文(京都大学大学院医学研
究科附属動物実験施設)
1. キーワード
高ビリルビン尿症、高ビリルビン血症、黄
疸、Dubin-Johnson syndrome、cMOAT
2. 由来
1983年、エーザイ株式会社安全性研究部で維持していたSlc:
SDを起源とする旋回ラット(Eisai Turning Rat: ETR)のF8世代目の個体中に黄疸症状を呈する個体が発見された。ETRは、4、5週令以
降になると、音や振動などの刺激によって自分の尻尾を追いかけるな旋回行動を起こ
す突然変異で、不完全優性遺伝を示す。この旋回形質に関わる遺伝子を除いた後、近
交系として確立し、高ビリルビン尿症ラット、Eisai hyperbilirubinuria
rat (EHBR)と名付けられた。
3. 表現型・病態
生後1日目より高ビリルビン血症および高ビリルビン尿症を
示し、生涯にわたり持続する。血漿中の総ビリルビンの約80%は抱合型ビリルビンで
ある。肝臓および腎臓は腫大し、緑色を帯びている。雌雄ともに妊性があり、兄妹交
配により維持し、近交系化されている。肝臓の組織所見ではHE染色で黄褐色を呈する
細胞質内色素顆粒が散在性に認められる。これは、ヒトのDubin-Johnson症候群の肝
細胞にみられる色素顆粒に類似している。
4. 病因(原因遺伝子)
常染色体性の単一劣性遺伝子(hyb)により支配され
ている。原因は、抱合型ビリルビンを肝細胞から胆汁中に分泌するATP依存性のトラ
ンスポーター、canalicular multispecific organic anion transporter (cMOAT)遺伝子の2564番目の塩基GがAに置き換わり、ストップコドンとなることによ
りおこる。
同座遺伝子にWistar由来のTR-およびGYがあり、ともにEHBR
と同様の症状を示す。TR-の原因遺伝子は、EHBRと同じくcMOAT遺伝子であるが、393
番目のアミノ酸をコードする塩基の一つが欠落し、フレームシフトが起こった結果、
401番目でストップコドンになることによる。
5. 臨床への応用、有用性
ヒトにおける先天性ビリルビン代謝異常で、直接型高ビリル
ビン血症を示すDubin-Johnson症候群のよい動物モデルとなる。
6. 維持機関
カワシマ商事
7. 文献
Inagaki T, Hoshino M, Ohara H, Yamada T, Ogasawara T,
Shimizu H, Itoh M
Decreased pancreatic exocrine function in the mutant Eisai
hyperbilirubinemic rat.
Pancreas. 1999 Mar;18(2):172-9.
Murata M, Tamai I, Sai Y, Nagata O, Kato H, Sugiyama Y,
Tsuji A
Hepatobiliary transport kinetics of HSR-903, a new
quinolone antibacterial agent.
Drug Metab Dispos. 1998 Nov;26(11):1113-9.
Kusuhara H, Han YH, Shimoda M, Kokue E, Suzuki H, Sugiyama
Y
Reduced folate derivatives are endogenous substrates for
cMOAT in rats.
Am J Physiol. 1998 Oct;275(4 Pt 1):G789-96.
Hirohashi T, Suzuki H, Ito K, Ogawa K, Kume K, Shimizu T,
Sugiyama Y
Hepatic expression of multidrug resistance-associated
protein-like proteins maintained in eisai hyperbilirubinemic rats.
Mol Pharmacol. 1998 Jun;53(6):1068-75.
Drummond GS, Kappas A
Sn-mesoporphyrin suppression of hyperbilirubinemia in
EHBR/Eis rats, an animal model of Dubin-Johnson syndrome.
Pharmacology. 1998 Mar;56(3):158-64.
Takikawa H, Sano N, Ogasawara T, Yamanaka M
Enhanced biliary excretion of lithocholate-3-sulfate by
ursodeoxycholate-3,7-disulfate infusion in Eisai hyperbilirubinemic rat (EHBR).
Dig Dis Sci. 1998 Jan;43(1):188-92.
Sasabe H, Tsuji A, Sugiyama Y
Carrier-mediated mechanism for the biliary excretion of
the quinolone antibiotic grepafloxacin and its glucuronide in rats.
J Pharmacol Exp Ther. 1998 Mar;284(3):1033-9.
Geng W, Schwab AJ, Horie T, Goresky CA, Pang KS
Hepatic uptake of bromosulfophthalein-glutathione in
perfused Eisai hyperbilirubinemic mutant rat liver: a multiple-indicator dilution study.
J Pharmacol Exp Ther. 1998 Feb;284(2):480-92.
Fukumura S, Takikawa H, Yamanaka M
Effects of organic anions and bile acid conjugates on
biliary excretion of pravastatin in the rat.
Pharm Res. 1998 Jan;15(1):72-6.
Keppler D, Konig J, Buchler M
The canalicular multidrug resistance protein, cMRP/MRP2, a
novel conjugate export pump expressed in the apical membrane of hepatocytes.
Adv Enzyme Regul. 1997;37:321-33.
Niinuma K, Takenaka O, Horie T, Kobayashi K, Kato Y,
Suzuki H, Sugiyama Y
Kinetic analysis of the primary active transport of
conjugated metabolites across the bile canalicular membrane: comparative study of
S-(2,4-dinitrophenyl)-glutathione and
6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole glucuronide.
J Pharmacol Exp Ther. 1997 Aug;282(2):866-72.
Takikawa H, Sano N, Sato A, Yamanaka M
Effect of taurolithocholate-3-sulphate on biliary
excretion of sulphobromophthalein and dibromosulphophthalein in the Eisai
hyperbilirubinaemic rat.
J Gastroenterol Hepatol. 1997 Jul;12(7):528-31.
Yamada T, Niinuma K, Lemaire M, Terasaki T, Sugiyama Y
Carrier-mediated hepatic uptake of the cationic
cyclopeptide, octreotide, in rats. Comparison between in vivo and in vitro.
Drug Metab Dispos. 1997 May;25(5):536-43.
Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y
Multispecific organic anion transporter is responsible for
the biliary excretion of the camptothecin derivative irinotecan and its metabolites in
rats.
J Pharmacol Exp Ther. 1997 Apr;281(1):304-14.
Yamaguchi Y, Hamaguchi H, Yamada S, Fujiwara K, Higashio
K, Miyanari N, Ichiguchi O, Goto M, Mori K, Ogawa M
Recombinant human hepatocyte growth factor facilitates
biliary transport after hepatocyte transplantation in Eisai hyperbilirubinemic rats.
Dig Dis Sci. 1997 Mar;42(3):522-8.
Ishizuka H, Konno K, Naganuma H, Sasahara K, Kawahara Y,
Niinuma K, Suzuki H, Sugiyama Y
Temocaprilat, a novel angiotensin-converting enzyme
inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is
deficient in Eisai hyperbilirubinemic mutant rats (EHBR).
J Pharmacol Exp Ther. 1997 Mar;280(3):1304-11.
Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama
Y
Molecular cloning of canalicular multispecific organic
anion transporter defective in EHBR.
Am J Physiol. 1997 Jan;272(1 Pt 1):G16-22.
Shimamura H, Suzuki H, Tagaya O, Horie T, Sugiyama Y
Biliary excretion of glycyrrhizin in rats: kinetic basis
for multiplicity in bile canalicular transport of organic anions.
Pharm Res. 1996 Dec;13(12):1833-7.
Yamada T, Niinuma K, Lemaire M, Terasaki T, Sugiyama Y
Mechanism of the tissue distribution and biliary excretion
of the cyclic peptide octreotide.
J Pharmacol Exp Ther. 1996 Dec;279(3):1357-64.
Yamazaki M, Kobayashi K, Sugiyama Y
Primary active transport of pravastatin across the liver
canalicular membrane in normal and mutant Eisai hyperbilirubinaemic rats.
Biopharm Drug Dispos. 1996 Nov;17(8):645-59.
Sugawara N, Lai Y, Yuasa M, Dhar SK, Arizono K
Biliary excretion of copper, manganese, and horseradish
peroxidase in Eisai hyperbilirubinemic mutant rats (EHBRs) with defective biliary
excretion of glutathione.
Biol Trace Elem Res. 1996 Oct-Nov;55(1-2):181-9.
Yamazaki M, Kobayashi K, Sugiyama Y
Primary active transport of pravastatin across the liver
canalicular membrane in normal and mutant Eisai hyperbilirubinemic rats.
Biopharm Drug Dispos. 1996 Oct;17(7):607-21.
Lu SC, Cai J, Kuhlenkamp J, Sun WM, Takikawa H, Takenaka
O, Horie T, Yi J, Kaplowitz N
Alterations in glutathione homeostasis in mutant Eisai
hyperbilirubinemic rats.
Hepatology. 1996 Jul;24(1):253-8.
Oguro T, Kaneko E, Kaneko Y, Numazawa S, Imaoka S, Funae
Y, Mikami T, Yoshida T
Suppressed expression of phenobarbital-inducible hepatic
cytochrome P-450s in Eisai-hyperbilirubinuria rats (EHBR/Eis).
J Pharmacol Exp Ther. 1996 Jun;277(3):1676-84.
Takikawa H, Yamazaki R, Sano N, Yamanaka M
Biliary excretion of estradiol-17 beta-glucuronide in the
rat.
Hepatology. 1996 Mar;23(3):607-13.
Takenaka O, Horie T, Kobayashi K, Suzuki H, Sugiyama
Kinetic analysis of hepatobiliary transport for conjugated
metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugated
hyperbilirubinemia.
Pharm Res. 1995 Nov;12(11):1746-55.
Ballatori N, Gatmaitan Z, Truong AT
Impaired biliary excretion and whole body elimination of
methylmercury in rats with congenital defect in biliary glutathione excretion.
Hepatology. 1995 Nov;22(5):1469-73.
Takenaka O, Horie T, Suzuki H, Sugiyama Y
Different biliary excretion systems for glucuronide and
sulfate of a model compound; study using Eisai hyperbilirubinemic rats.
J Pharmacol Exp Ther. 1995 Sep;274(3):1362-9.
Takikawa H, Nishikawa K, Sano N, Yamanaka M, Horie T
Mechanisms of biliary excretion of lithocholate-3-sulfate
in Eisai hyperbilirubinemic rats (EHBR).
Dig Dis Sci. 1995 Aug;40(8):1792-7.
Yamazaki K, Mikami T, Hosokawa S, Tagaya O, Nozaki Y,
Kawaguchi A, Funami H, Katoh H, Yamamoto N, Wakabayashi T
A new mutant rat with hyperbilirubinuria (hyb).
J Hered. 1995 Jul-Aug;86(4):314-7.
Hamaguchi H, Yamaguchi Y, Goto M, Misumi M, Hisama N,
Miyanari N, Mori K, Ogawa M
Hepatic biliary transport after hepatocyte transplantation
in Eizai hyperbilirubinemic rats.
Hepatology. 1994 Jul;20(1 Pt 1):220-4.
Kawaguchi A, Nozaki Y, Hosokawa S, Tagaya O, Mikami T,
Wakabayashi T
Establishment of hyperbilirubinuria rat mutant--a new
animal model for jaundice.
Exp Anim. 1994 Jan;43(1):37-44.
Takikawa H, Minagawa K, Sano N, Yamanaka M
Lithocholate-3-O-glucuronide-induced cholestasis. A study
with congenital hyperbilirubinemic rats and effects of ursodeoxycholate conjugates.
Dig Dis Sci. 1993 Aug;38(8):1543-8.
Sathirakul K, Suzuki H, Yasuda K, Hanano M, Tagaya O,
Horie T, Sugiyama Y
Kinetic analysis of hepatobiliary transport of organic
anions in Eisai hyperbilirubinemic mutant rats.
J Pharmacol Exp Ther. 1993 Jun;265(3):1301-12.
Dhar SK, Takiguchi M, Arizono K, Ariyoshi T, Wakabayashi T
Nature of heme metabolizing enzymes in a mutant rat with
hyperbilirubinuria.
Res Commun Chem Pathol Pharmacol. 1993 Jun;80(3):329-36.
Yamashita G, Tazuma S, Horikawa K, Aihara N, Ochi H,
Teramen K, Yamashita Y, Sasaki M, Ohya T, Kajiyama G
Partial characterization of mechanism(s) by which
sulphobromophthalein reduces biliary lipid secretion.
Biochem J. 1993 Apr 1;291 ( Pt 1):173-7.
Takikawa H, Sano N, Wako Y, Yamanaka M
Effects of organic anions and bile acids on biliary lipid
excretion in hyperbilirubinemic mutant Sprague-Dawley rats.
J Hepatol. 1993 Feb;17(2):247-52.
Sano N, Takikawa H, Yamanaka M
Estradiol-17 beta-glucuronide-induced cholestasis. Effects
of ursodeoxycholate-3-O-glucuronide and 3,7-disulfate.
J Hepatol. 1993 Feb;17(2):241-6.
Adachi Y, Kobayashi H, Shouji M, Kitano M, Okuyama Y,
Yamamoto T
Functional integrity of hepatocyte canalicular membrane
transport of taurocholate and bilirubin diglucuronide in Eisai hyperbilirubinuria rats.
Life Sci. 1993;52(9):777-84.
Kitamura T, Alroy J, Gatmaitan Z, Inoue M, Mikami T,
Jansen P, Arias IM
Defective biliary excretion of epinephrine metabolites in
mutant (TR-) rats: relation to the pathogenesis of black liver in the Dubin-Johnson
syndrome and Corriedale sheep with an analogous excretory defect.
Hepatology. 1992 Jun;15(6):1154-9.
Takikawa H, Sano N, Minagawa K, Yamanaka M
Effects of ursodeoxycholate, its glucuronide and disulfate
and beta-muricholate on biliary bicarbonate concentration and biliary lipid excretion.
J Hepatol. 1992 May;15(1-2):77-84.
Hosokawa S, Tagaya O, Mikami T, Nozaki Y, Kawaguchi A,
Yamatsu K, Shamoto M
A new rat mutant with chronic conjugated
hyperbilirubinemia and renal glomerular lesions.
Lab Anim Sci. 1992 Feb;42(1):27-34.
Fernandez-Checa JC, Takikawa H, Horie T, Ookhtens M,
Kaplowitz N
Canalicular transport of reduced glutathione in normal and
mutant Eisai hyperbilirubinemic rats.
J Biol Chem. 1992 Jan 25;267(3):1667-73.
Ohmori S, Kuriya S, Uesugi T, Horie T, Sagami F, Mikami T,
Kawaguchi A, Rikihisa T, Kanakubo Y
Decrease in the specific forms of cytochrome P-450 in
liver microsomes of a mutant strain of rat with hyperbilirubinuria.
Res Commun Chem Pathol Pharmacol. 1991 May;72(2):243-53.
Kurisu H, Kamisaka K, Koyo T, Yamasuge S, Igarashi H,
Maezawa H, Uesugi T, Tagaya O
Organic anion transport study in mutant rats with
autosomal recessive conjugated hyperbilirubinemia.
Life Sci. 1991;49(14):1003-11.
Nakamura T, Satoh T, Horie T, Sagami F, Tagaya O
Strain differences of rat liver carboxylesterase
activities related to the phenotype difference of esterase-3 (egasyn).
Res Commun Chem Pathol Pharmacol. 1989 Dec;66(3):451-9.
Mikami T, Nozaki T, Tagaya S, Hosokawa S, Nakura T, Hori
H, Kondou S
The characteristics of a new mutant rat with
hyperbilirubinuria syndrome.
Congenital Anom. 1986;26:250-1.