Effect of genipin on cholestasis induced by estradiol‐17β‐glucuronide and lithocholate‐3‐O‐glucuornide in rats

Goto, Hideaki; Takikawa, Hajime

doi:10.1111/j.1872-034x.2010.00630.x

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Indeed, the expression levels of the metabolic enzyme UGT1A1 and eight transporters including MRP2, BSEP, OCT1, NTCP, MDR1, OATP1A1, OATP1A2, and OATP1A4, were all down-regulated significantly in cholestatic model rats when compared with normal rats. The results indicate that UGT1A1, MRP2, BSEP, OCT1, NTCP, OATP1A2, and OATP1A4 can be used as potential biological markers for evaluating the ameliorative effects of YCHD in cholestasis, and considering that the metabolism of drugs and endogenous substances (like bilirubin, bile acid, and so on) are related to metabolic enzyme of UGT1A1 and transporter protein of OATP1B1, MRP2 in liver ( Cui et al, 2009 ; Vitek and Ostrow, 2009 ; Goto and Takikawa, 2010 ), these enzymes directly affect the metabolic process of YCHD and bilirubin. Moreover, different doses of YCHD can have different effects on cholestasis, which can also be reflected by decreased levels of serum biochemistry.…”

Section: Discussionmentioning

confidence: 99%

Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters

Ding

Zhang

et al. 2018

Front. Pharmacol.

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Yinchenhao Decoction (YCHD), a famous traditional Chinese formula, has been used for treating cholestasis for 1000s of years. The cholagogic effect of YCHD has been widely reported, but its pharmacodynamic material and underlying therapeutic mechanism remain unclear. By using ultra-high-performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry, 11 original active components and eight phase II metabolites were detected in rats after oral administration of YCHD, including three new phase II metabolites. And it indicated that phase II metabolism was one of the major metabolic pathway for most active components in YCHD, which was similar to the metabolism process of bilirubin. It arouses our curiosity that whether the metabolism process of YCHD has any relationship with its cholagogic effects. So, a new method for simultaneous quantitation of eight active components and four phase II metabolites of rhein, emodin, genipin, and capillarisin has been developed and applied for their pharmacokinetic study in both normal and alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis rats. The results indicated the pharmacokinetic behaviors of most components of YCHD were inhibited, which was hypothesized to be related to different levels of metabolic enzymes and transporters in rat liver. So dynamic changes of intrahepatic enzyme expression in cholestasis and YCHD treated rats have been monitored by an UHPLC-tandem mass spectrometry method. The results showed expression levels of UDP-glucuronosyltransferase 1-1 (UGT1A1), organic anion-transporting polypeptide 1A4 (OATP1A4), multidrug resistance-associated protein 2 (MRP2), multidrug resistance protein 1, sodium-dependent taurocholate cotransporter, and organic anion-transporting polypeptide 1A2 were significantly inhibited in cholestasis rats, which would account for reducing the drug absorption and the metabolic process of YCHD in cholestatic rats. A high dose (12 g/kg) of YCHD remarkably increased the expression of UGT1A1, bile salt export pump, MRP2, OATP1A4 in cholestasis rats presented it exhibited the greatest ameliorative effect on cholestasis, also particularly in histopathological examination and reducing levels of alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, and total bile acid. Considering the metabolic process of bilirubin in vivo, the choleretic effect of YCHD is proven to be related to its regulatory action on expression of metabolic enzymes and transporters in cholestatic liver.

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Section: Discussionmentioning

confidence: 99%

Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters

Ding

Zhang

et al. 2018

Front. Pharmacol.

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“…We previously reported that genipin inhibited biliary EM excretion and cholestasis induced by E17G [22]; however, PCG had no effect on biliary EM excretion and E17G cholestasis (Figs. 5, 6).…”

Section: Discussionmentioning

confidence: 99%

“…2). Furthermore, PCG may not bind to P‐gp and cause its conformational change, as has been speculated with genipin [22].…”

Section: Discussionmentioning

confidence: 99%

Effect of penicillin G on the biliary excretion of cholephilic compounds in rats

Fukami

Tanka

Takikawa

2011

J Hepato Biliary Pancreat

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It was shown that colchicine-sensitive vesicular transport has no role on the penicillin G-induced insertion of Mrp2 into the canalicular membrane, as has been observed with genipin. Although the choleresis of penicillin G is thought to be due to the increased biliary excretion of glutathione and penicillin G itself by Mrp2, the mechanism of Mrp2 insertion by penicillin G is thought to be partly different from that by genipin.

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“…In our laboratory, geniposide could be transformed into genipin by immobilized β -Glucosidase in a two-phase aqueous-organic system [2]. Genipin has been proven to possess multiple bioactivities including antitumor [3, 4], neuroprotective [5], choleretic [6], and anti-inflammatory effects [7–9]. It is also an excellent natural cross-linker for proteins, collagen, gelatin, and chitosan cross-linking.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Genipin in Rat and Identification of Metabolites by Using Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Tandem Mass Spectrometry

Ding

Hou

Zhang

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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The in vivo and in vitro metabolism of genipin was systematically investigated in the present study. Urine, plasma, feces, and bile were collected from rats after oral administration of genipin at a dose of 50 mg/kg body weight. A rapid and sensitive method using ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF MS) was developed for analysis of metabolic profile of genipin in rat biological samples (urine, plasma, feces, and bile). A total of ten metabolites were detected and identified by comparing their fragmentation patterns with that of genipin using MetaboLynx software tools. On the basis of the chromatographic peak area, the sulfated and glucuronidated conjugates of genipin were identified as major metabolites. And the existence of major metabolites G1 and G2 was confirmed by the in vitro enzymatic study further. Then, metabolite G1 was isolated from rat bile by semipreparative HPLC. Its structure was unambiguously identified as genipin-1-o-glucuronic acid by comparison of its UV, IR, ESI-MS, 1H-NMR, and 13C-NMR spectra with conference. In general, genipin was a very active compound that would transform immediately, and the parent form of genipin could not be observed in rats biological samples. The biotransformation pathways of genipin involved demethylated, ring-opened, cysteine-conjugated, hydroformylated, glucuronidated, and sulfated transformations.

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Effect of genipin on cholestasis induced by estradiol‐17β‐glucuronide and lithocholate‐3‐O‐glucuornide in rats

Abstract: Genipin protected estradiol-17beta-glucuronide-induced cholestasis. The mechanism of the protection of cholestasis by genipin is unknown, but it is speculated to be due to a conformational change of P-gp by genipin, in addition to the stimulation of Mrp2 insertion into the bile canaliculi.

Cited by 8 publications

References 41 publications

Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters

Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters

Effect of penicillin G on the biliary excretion of cholephilic compounds in rats

Metabolism of Genipin in Rat and Identification of Metabolites by Using Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Tandem Mass Spectrometry

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