Identification of UDP-glucuronosyltransferases 1A1, 1A3 and 2B15 as the main contributors to glucuronidation of bakuchiol, a natural biologically active compound.
1. Bakuchiol, one of the main active compounds of Psoralea corylifolia, possesses a variety of pharmacological activities such as anti-tumor and anti-aging effects. Here, we aimed to characterize the glucuronidation of bakuchiol using human liver microsomes (HLM) and expressed UDP-glucuronosyltransferase (UGT) enzymes. 2. The glucuronide of bakuchiol was confirmed by liquid chromatography-mass spectrometry (LC-MS) and β-glucuronidase hydrolysis assay. Glucuronidation rates and kinetic parameters were derived by enzymatic incubation and model fitting. Activity correlation analyses were performed to identify the main UGT isoforms contributing to hepatic metabolism of bakuchiol. 3. Among the three UGT enzymes (i.e., UGT1A1, UGT1A3 and UGT2B15) capable of catalyzing bakuchiol glucuronidation, UGT2B15 showed the highest activity with a CLintvalue of 100 μl/min/nmol. Bakuchiol glucuronidation was strongly correlated with glucuronidation of 5-hydroxyrofecoxib (r = 0.933; p < 0.001), 3-O-glucuronidation of β-estradiol (r = 0.719; p < 0.01) and significantly correlated with 24-O-glucuronidation of CDCA (r = 0.594; p < 0.05). In addition, a marked species difference existed in hepatic glucuronidation of bakuchiol. 4. In conclusion, UGT1A1, UGT1A3 and UGT2B15 were identified as the main contributors to glucuronidation of bakuchiol.
a Guangzhou Jinan Biomedicine Research and Development Center, Jinan University , Guangzhou , China.
Feng
F
Li
b Division of Pharmaceutics , College of Pharmacy, Jinan University , Guangzhou , China , and.
Shuai
S
Wang
b Division of Pharmaceutics , College of Pharmacy, Jinan University , Guangzhou , China , and.
Danyi
D
Lu
a Guangzhou Jinan Biomedicine Research and Development Center, Jinan University , Guangzhou , China.
Yifei
Y
Wang
c Ocular Surface Research Center and Institute of Ophthalmology, Jinan University School of Medicine , Guangzhou , China.
Dong
D
Dong
b Division of Pharmaceutics , College of Pharmacy, Jinan University , Guangzhou , China , and.
Baojian
B
Wu
D002853:Chromatography, Liquid; D005966:Glucuronidase / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D007783:Lactones; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D010636:Phenols / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D005966:Glucuronidase; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D007783:Lactones; D010636:Phenols; D010936:Plant Extracts; D000099148:UGT1A1 Enzyme; C445439:5-hydroxyrofecoxib; C012765:bakuchiol
Activity correlation; UGT; bakuchiol; glucuronidation; species difference