Evaluation of the inhibition risk of shikonin on human and rat UDP-glucuronosyltransferases (UGT) through the cocktail approach. (15th September 2019)

• Record Type: Journal Article
• Authors: Cheng, Yi; Tang, Shuowen; Chen, Ang; Zhang, Yuanjin; Liu, Mingyao; Wang, Xin
• Is Part Of: Toxicology letters. Volume 312(2019)
• Page Start: 214
• Page End: 221
• Publication Date: 2019-09-15
• Subjects: Estradiol (PubChem CID: 5757) -- Chenodeoxycholic acid (PubChem CID: 10133) -- Serotonin (PubChem CID: 5202) -- Propofol (PubChem CID: 4943) -- Zidovudine (PubChem CID: 35370); CYP cytochrome P450 -- UGT UDP-glucuronosyltransferases -- DDI drug-drug interactions -- HLMs human liver microsomes -- RLMs rat liver microsomes -- PROG propofol glucuronide -- AZTG 3-azido-3-deoxythymidine glucuronidation -- LC-MS/MS liquid chromatography–tandem mass spectrometry; Shikonin -- UDP-glucuronosyltransferases (UGT) -- Cocktail method -- Human liver microsomes -- Reversible inhibitor; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.05.017
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: The inhibition risk of shikonin on UGT enzymes was firstly investigated. Shikonin significantly inhibited UGT1A1, UGT1A3, UGT1A9/PROG, and UGT2B7/AZTG activities in human and rat liver microsomes. Shikonin exhibited no time-dependent inhibition on UGT activities. Shikonin displayed competitive inhibition on UGT isoforms. Abstract: Shikonin, a natural red colorant, is widely used for food garnishment and cosmetic ingredient in the world. Shikonin also possesses a variety of pharmacological actions, including anti-inflammation and anti-cancer activities. However, little is known about its effects on the UDP-glucuronosyltransferases (UGT) activity. Therefore, the aim of this study was to evaluate the effect of shikonin on the UGT1A1, UGT1A3, UGT1A6, UGT1A9 and UGT2B7 activities via the human and rat liver microsomal assay and cocktail approach. The results showed shikonin inhibited human and rat liver microsomal UGT activity only in a dose-dependent manner. The further enzyme kinetic studies demonstrated that shikonin was not only a competitive inhibitor of human UGT1A1, UGT1A9, and UGT2B7, but also presented competitive inhibition on rat UGT1A1 and AZTG reactions. In conclusion, shikonin as a reversible inhibitor of UGT enzyme has a high-risk potential to cause the possible toxicity, especially drug-drug or food-drug interactions.