Danning Tablets Attenuates α-naphthylisothiocyanate-induced Cholestasis by Modulating the Expression of Transporters and Metabolic Enzymes

Overview

Journal BMC Complement Altern Med

Publisher Biomed Central

Specialty Rehabilitation Medicine

Date 2014 Jul 19

PMID 25033983

Citations 8

Authors

Lili Ding

Binfeng Zhang

Changsen Zhan

Li Yang

Zhengtao Wang

Affiliations

Soon will be listed here.

Abstract

Background: The 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.

Methods: Danning 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.

Results: In 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.

Conclusions: DNts might promote bile acid and bilirubin elimination by regulating the expressions of hepatic and renal transporters as well as hepatic metabolic enzymes.

Citing Articles

Livogrit mitigates ANIT-induced cholestasis-like symptoms in an model by curbing hepatic inflammation and regulating BAX, TGF-β, MMP-9 and α-SMA gene expression.

Balkrishna A, Paliwal R, Singh S, Singh R, Gohel V, Dev R Heliyon. 2025; 11(3):e41855.

PMID: 39944325 PMC: 11815894. DOI: 10.1016/j.heliyon.2025.e41855.

How traditional Chinese medicine can prevent recurrence of common bile duct stones after endoscopic retrograde cholangiopancreatography?.

Bian H, Zhang L, Yao Y, Lv F, Wei J Front Pharmacol. 2024; 15:1363071.

PMID: 38659575 PMC: 11039848. DOI: 10.3389/fphar.2024.1363071.

Chishao () alleviates intra-hepatic cholestasis by modulating NTCP in rats.

Sun X, Fang J, Fang N Front Pharmacol. 2024; 15:1341651.

PMID: 38362143 PMC: 10867832. DOI: 10.3389/fphar.2024.1341651.

The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes.

Han J, Wu P, Wen Y, Liu C, Liu X, Tao H Front Pharmacol. 2023; 14:1280864.

PMID: 37881184 PMC: 10597705. DOI: 10.3389/fphar.2023.1280864.

Network Pharmacology-Based Investigation of the Therapeutic Mechanisms of Action of Danning Tablets in Nonalcoholic Fatty Liver Disease.

Lin T, Li L, Liang C, Peng L Evid Based Complement Alternat Med. 2021; 2021:3495360.

PMID: 33995543 PMC: 8096548. DOI: 10.1155/2021/3495360.

References

Yang P, Chen P, Wang T, Zhan Y, Zhou M, Xia L . Loss of A(1) adenosine receptor attenuates alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice. Toxicol Sci. 2012; 131(1):128-38. DOI: 10.1093/toxsci/kfs263. View

Stieger B . The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol. 2010; (201):205-59. DOI: 10.1007/978-3-642-14541-4_5. View

Chen X, Zhang C, Wang H, Xu J, Duan Z, Zhang Y . Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice. Toxicol Appl Pharmacol. 2009; 240(1):26-36. DOI: 10.1016/j.taap.2009.06.022. View

Dombrowski F, Kubitz R, Chittattu A, Wettstein M, Saha N, Haussinger D . Electron-microscopic demonstration of multidrug resistance protein 2 (Mrp2) retrieval from the canalicular membrane in response to hyperosmolarity and lipopolysaccharide. Biochem J. 2000; 348 Pt 1:183-8. PMC: 1221052. View

Wagner M, Fickert P, Zollner G, Fuchsbichler A, Silbert D, Tsybrovskyy O . Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology. 2003; 125(3):825-38. DOI: 10.1016/s0016-5085(03)01068-0. View

Kliewer S, Willson T . Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor. J Lipid Res. 2002; 43(3):359-64. View

Trauner M, Meier P, Boyer J . Molecular pathogenesis of cholestasis. N Engl J Med. 1998; 339(17):1217-27. DOI: 10.1056/NEJM199810223391707. View

Calvo J, Reiter R, Garcia J, Ortiz G, Tan D, Karbownik M . Characterization of the protective effects of melatonin and related indoles against alpha-naphthylisothiocyanate-induced liver injury in rats. J Cell Biochem. 2001; 80(4):461-70. DOI: 10.1002/1097-4644(20010315)80:4<461::aid-jcb1000>3.0.co;2-p. View

Plaa G, Priestly B . Intrahepatic cholestasis induced by drugs and chemicals. Pharmacol Rev. 1976; 28(3):207-73. View

10.

Cui Y, Aleksunes L, Tanaka Y, Goedken M, Klaassen C . Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. Toxicol Sci. 2009; 110(1):47-60. PMC: 2696329. DOI: 10.1093/toxsci/kfp094. View

11.

Halilbasic E, Claudel T, Trauner M . Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol. 2012; 58(1):155-68. PMC: 3526785. DOI: 10.1016/j.jhep.2012.08.002. View

12.

Xu C, Li C, Kong A . Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res. 2005; 28(3):249-68. DOI: 10.1007/BF02977789. View

13.

Shelby M, Cherrington N, Vansell N, Klaassen C . Tissue mRNA expression of the rat UDP-glucuronosyltransferase gene family. Drug Metab Dispos. 2003; 31(3):326-33. DOI: 10.1124/dmd.31.3.326. View

14.

Meyer U . Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm. 1996; 24(5):449-59. DOI: 10.1007/BF02353473. View

15.

Hill H, Straka J . Protein determination using bicinchoninic acid in the presence of sulfhydryl reagents. Anal Biochem. 1988; 170(1):203-8. DOI: 10.1016/0003-2697(88)90109-1. View

16.

Takikawa H . Hepatobiliary transport of bile acids and organic anions. J Hepatobiliary Pancreat Surg. 2002; 9(4):443-7. DOI: 10.1007/s005340200055. View

17.

Ding L, Zhang B, Dou W, Yang L, Zhan C, Wang Z . Protective effect of Danning tablet on acute livery injury with cholestasis induced by α-naphthylisothiocyanate in rats. J Ethnopharmacol. 2012; 140(2):222-9. DOI: 10.1016/j.jep.2011.12.047. View

18.

BECKER B, Plaa G . The nature of alpha-naphthylisothiocyanate-induced cholestasis. Toxicol Appl Pharmacol. 1965; 7(5):680-5. DOI: 10.1016/0041-008x(65)90125-0. View

19.

Banoglu E . Current status of the cytosolic sulfotransferases in the metabolic activation of promutagens and procarcinogens. Curr Drug Metab. 2001; 1(1):1-30. DOI: 10.2174/1389200003339234. View

20.

Dean M, Hamon Y, Chimini G . The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 2001; 42(7):1007-17. View