Abstract
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.
Highlights
As one of the top 15 causes of death in the United States (Yang et al, 2009), intrahepatic cholestasis is a common clinical pathological process of the liver that can be induced by drugs, hormones, cytokines, stones, and progressive bile duct or liver cell destruction
The results shows that ANIT induced cholestasis is associated with down-regulation of UGT1A1, multidrug resistanceassociated protein 2 (MRP2), bile salt export pump (BSEP), organic cation transporter 1 (OCT1), NTCP, multidrug resistance protein 1 (MDR1), OATP1A1, OATP1A2, and OATP1A4 and Yinchenhao Decoction (YCHD) can up-regulate UGT1A1, MRP2, BSEP, OATP1A2, OATP1A4, OCT1, and NTCP during the ameliorative effect of cholestasis
conjugated bilirubin (CB) can be transported through multidrug resistanceassociated protein 2 (MRP2) on the capillary bile duct membrane of hepatocytes into the capillary bile duct, discharged into the small intestine with bile, and excreted through the intestine
Summary
As one of the top 15 causes of death in the United States (Yang et al, 2009), intrahepatic cholestasis is a common clinical pathological process of the liver that can be induced by drugs, hormones, cytokines, stones, and progressive bile duct or liver cell destruction. It increases the risk of liver failure and cirrhosis periductular fibrosis, biliary fibrosis, cirrhosis (Hirschfield et al, 2010), or other hepatic and gall-bladder diseases (Liu et al, 2015). Despite research into its curative effects, the pharmacodynamic material basis and underlying therapeutic mechanism remain unclear
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