Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice

Chen, Xi; Zhang, Cheng; Wang, Hua; Xu, Jian; Duan, Zi-Hao; Zhang, Ying; Yu, Tao; Wei, Wei; Xu, Dexiang; Xu, Jianming

doi:10.1016/j.taap.2009.06.022

Cited by 32 publications

(21 citation statements)

References 36 publications

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“…As proof of concept, the oatp and mrp2 inhibitor rifampicin and the ntcp and bsep inhibitor bosentan were administered to FVB-mice and subjected to a PET-scan with [ 18 F]FCA. Both rifampicin and bosentan caused a significant delay in hepatic uptake and lower maximum % ID in the liver and both drugs gave rise to an increased amount of [ 18 F]FCA in arterial blood, which is in line with an observed increase in serum bile acids after administration of these drugs [19,22]. When an identical dose of rifampicin was administered to FVB-mice scanned with 99m Tc mebrofenin [33], a complete block of canalicular efflux was observed on the SPECT-scan, whereas [ 18 F]FCA excretion into bile is only hindered.…”

Section: Discussionmentioning

confidence: 71%

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

et al. 2017

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IntroductionDrug-induced cholestasis is a liver disorder that might be caused by interference of drugs with the hepatobiliary bile acid transporters. It is important to identify this interference early on in drug development. In this work, Positron Emission Tomography (PET)-imaging with a 18F labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids.Methods3β-[18F]fluorocholic acid ([18F]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [18F]fluoride, followed by deprotection with sodium hydroxide. Transport of [18F]FCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [18F]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [18F]FCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic μPET scanning.ResultsRadiosynthesis of [18F]FCA was achieved in a moderate radiochemical yield (8.11 ± 1.94%; non-decay corrected; n = 10) and high radiochemical purity (>99%). FCA was transported by the basolateral bile acid uptake transporters NTCP, OATP1B1 and OATP1B3. For canalicular efflux, BSEP and MRP2 are the relevant bile acid transporters. [18F]FCA was found to be metabolically stable. In vivo, [18F]FCA showed fast hepatic uptake (4.5 ± 0.5 min to reach 71.8 ± 1.2% maximum % ID) and subsequent efflux to the gallbladder and intestines (93.3 ± 6.0% ID after 1 hour). Hepatobiliary transport of [18F]FCA was significantly inhibited by both rifampicin and bosentan.ConclusionA 18F labeled bile acid analogue, [18F]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [18F]FCA can be used as a probe to monitor disturbed hepatobiliary transport in vivo and accumulation of bile acids in blood and liver during drug development.

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Section: Discussionmentioning

confidence: 71%

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

et al. 2017

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“…Our previous study demonstrated that rifampicin, one of the most commonly used anti-tubercular drugs, caused intrahepatic cholestasis [15]. The present study investigated the effects of rifampicin on hepatic lipid metabolism in mice.…”

Section: Discussionmentioning

confidence: 95%

“…An earlier study demonstrates that oxidative stress in the mitochondria is involved in the pathogenesis of rifampicin plus isoniazid-induced apoptotic liver cell injury in mice [14]. According to a report from our laboratory, rifampicin causes intrahepatic cholestasis through altering integrity of hepatocyte ZO-1 and occluding [15]. …”

Section: Introductionmentioning

confidence: 99%

Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver

Huang

Zhang

et al. 2016

PLoS ONE

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Previous study found that rifampicin caused intrahepatic cholestasis. This study investigated the effects of rifampicin on hepatic lipid metabolism. Mice were orally administered with rifampicin (200 mg/kg) daily for different periods. Results showed that serum TG level was progressively reduced after a short elevation. By contrast, hepatic TG content was markedly increased in rifampicin-treated mice. An obvious hepatic lipid accumulation, as determined by Oil Red O staining, was observed in mice treated with rifampicin for more than one week. Moreover, mRNA levels of Fas, Acc and Scd-1, several key genes for fatty acid synthesis, were elevated in rifampicin-treated mice. In addition, the class B scavenger receptor CD36 was progressively up-regulated by rifampicin. Interestingly, hepatic SREBP-1c and LXR-α, two important transcription factors that regulate genes for hepatic fatty acid synthesis, were not activated by rifampicin. Instead, hepatic PXR was rapidly activated in rifampicin-treated mice. Hepatic PPARγ, a downstream target of PXR, was transcriptionally up-regulated. Taken together, the increased hepatic lipid synthesis and uptake of fatty acids from circulation into liver jointly contribute to rifampicin-induced hepatic lipid accumulation. The increased uptake of fatty acids from circulation into liver might be partially attributed to rifampicin-induced up-regulation of PPARγ and its target genes.

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“…Bile acids were extracted from liver samples using 75% ethanol, as previously described [19]. Total bile acids in the liver, bile, and urine were measured using commercial assay kits from the Jiancheng Institute of Biotechnology (Nanjing, China).…”

Section: Methodsmentioning

confidence: 99%

Danning tablets attenuates α-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes

Ding

Zhang

Chen

et al. 2014

BMC Complement Altern Med

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BackgroundThe Danning tablets (DNts) is commonly prescribed in China as a cholagogic formula. Our previous studies showed that DNts exerted the protective effect on α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis in a dose-dependent mannar. However, the detailed molecular mechanisms of DNts against ANIT-induced cholestasis are still not fully explored.MethodsDanning tablet (3 g/kg body weight/day) was administered orally to experimental rats for seven days before they were treated with ANIT (60 mg/kg daily via gastrogavage) which caused cholestasis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and total bile acid (TBA) were measured to evaluate the protective effect of Danning tablet at 12, 24 and 48h after ANIT treatment. Meanwhile, total bilirubin or total bile acid in the bile, urine and liver were also measured at 48h after ANIT treatment. Furthermore, the hepatic or renal mRNA and protein levels of metabolic enzymes and transports were investigated to elucidate the protective mechanisms of Danning tablet against ANIT-induced cholestasis.ResultsIn this study, we found that DNts significantly attenuated translocation of multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane into an intracellular and up-regulated the hepatic mRNA and protein expressions of metabolic enzymes including cytochrome P450 2b1(Cyp2b1) and uridine diphosphate-5¢- glucuronosyltransferase (Ugt1a1)) and transporters including bile salt export pump (Bsep) and multidrug resistance protein 2 (Mdr2)) as well as renal organic solute transporter beta (Ostβ), accompanied by further increase in urinary and biliary excretion of bile acid and bilirubin.ConclusionsDNts might promote bile acid and bilirubin elimination by regulating the expressions of hepatic and renal transporters as well as hepatic metabolic enzymes.

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Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice

Cited by 32 publications

References 36 publications

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver

Danning tablets attenuates α-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes

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