Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions  

作　　者：LI Fei-Yan XIE Hao WENG Lin WANG Hong CAO Li-Juan HAO Hai-Ping WANG Guang-Ji 

机构地区：[1]State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University [2]Department of Good Clinical Practice, Zhejiang Cancer Hospital

出　　处：《Chinese Journal of Natural Medicines》2016年第7期534-540,共7页中国天然药物（英文版）

基　　金：supported by the Key Lab of Drug Metabolism and Pharmacokinetics of Jiangsu Province(No.BM2012012)

摘　　要：Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases(UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s(CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate(GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid(GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil （MMF）, an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases （UGTs）. Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s （CYPs）, few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate （GLN） on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGTIA protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT 1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid （GA） in liver and intestine and the inhibitory effects of GA on UGTIA activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

关 键 词：Diammonium glycyrrhizinate UDP-GLUCURONOSYLTRANSFERASE SPRAGUE-DAWLEY rat Drug-drug interaction 

分 类 号：R965[医药卫生—药理学]