Evaluation of the inhibition risk of shikonin on human and rat UDP-glucuronosyltransferases (UGT) through the cocktail approach

Yi Cheng; Shuowen Tang; Ang Chen; Yuanjin Zhang; Mingyao Liu; Xin Wang

doi:10.1016/j.toxlet.2019.05.017

Evaluation of the inhibition risk of shikonin on human and rat UDP-glucuronosyltransferases (UGT) through the cocktail approach

Toxicol Lett. 2019 Sep 15:312:214-221. doi: 10.1016/j.toxlet.2019.05.017. Epub 2019 May 23.

Authors

Yi Cheng¹, Shuowen Tang¹, Ang Chen¹, Yuanjin Zhang¹, Mingyao Liu², Xin Wang³

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
² Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, United States.
³ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. Electronic address: xwang@bio.ecnu.edu.cn.

PMID: 31128210
DOI: 10.1016/j.toxlet.2019.05.017

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.

Keywords: Chenodeoxycholic acid (PubChem CID: 10133); Cocktail method; Estradiol (PubChem CID: 5757); Human liver microsomes; Propofol (PubChem CID: 4943); Reversible inhibitor; Serotonin (PubChem CID: 5202); Shikonin; UDP-glucuronosyltransferases (UGT); Zidovudine (PubChem CID: 35370).

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / toxicity
Enzyme Inhibitors / toxicity
Gene Expression Regulation, Enzymologic / drug effects*
Glucuronosyltransferase / antagonists & inhibitors*
Glucuronosyltransferase / metabolism
Humans
Male
Microsomes, Liver / drug effects*
Microsomes, Liver / enzymology*
Molecular Structure
Naphthoquinones / toxicity*
Rats
Rats, Sprague-Dawley
Species Specificity

Substances

Anti-Inflammatory Agents, Non-Steroidal
Enzyme Inhibitors
Naphthoquinones
shikonin
Glucuronosyltransferase