Metabolism and disposition of corylifol A from <i>Psoralea corylifolia</i>: metabolite mapping, isozyme contribution, species differences and identification of efflux transporters for corylifol A-<i>O</i>-glucuronide in HeLa1A1 cells
Creators: name: Li, Yang
name: Xu, Jinjin
name: Xu, Chunxia
name: Qin, Zifei
name: Li, Shishi
name: Hu, Liufang
name: Yao, Zhihong
name: Gonzalez, Frank J.
name: Yao, Xinsheng
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Pharmacology
subject: Environmental Sciences not elsewhere classified
subject: Chemical Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Cancer
subject: Inorganic Chemistry
subject: FOS: Chemical sciences
subject: Hematology
subject: Virology

description: Corylifol A (CA), a phenolic compound from <i>Psoralea corylifolia</i>, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA.Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene silencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition.Three oxidated metabolites (M1–M3) and two glucuronides (M4–M5) were detected. The intrinsic clearances (<i>CL</i><sub>int</sub>) values of M1 and M4 in HLM were 48.10 and 184.03 μL/min/mg, respectively. Additionally, CYP1A1, 2C8 and 2C19 were identified as main contributors with <i>CL</i><sub>int</sub> values of 13.01–49.36 μL/min/mg, while UGT1A1, 1A7, 1A8 and 1A9 were with <i>CL</i><sub>int</sub> values ranging from 85.01 to 284.07 μL/min/mg. Furthermore, activity correlation analysis proved CYP2C8, UGT1A1 and 1A9 were the main active hepatic isozymes. Besides, rats and monkeys were appropriate model animals. Moreover, dipyridamole and MK571 both could significantly inhibit M4 efflux. Gene silencing results also indicated MRP4 and BCRP were major contributors in HeLa1A1 cells.Taken together, CYPs, UGTs, MRP4 and BCRP were important determinants of CA pharmacokinetics. Corylifol A (CA), a phenolic compound from <i>Psoralea corylifolia</i>, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA. Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene silencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition. Three oxidated metabolites (M1–M3) and two glucuronides (M4–M5) were detected. The intrinsic clearances (<i>CL</i><sub>int</sub>) values of M1 and M4 in HLM were 48.10 and 184.03 μL/min/mg, respectively. Additionally, CYP1A1, 2C8 and 2C19 were identified as main contributors with <i>CL</i><sub>int</sub> values of 13.01–49.36 μL/min/mg, while UGT1A1, 1A7, 1A8 and 1A9 were with <i>CL</i><sub>int</sub> values ranging from 85.01 to 284.07 μL/min/mg. Furthermore, activity correlation analysis proved CYP2C8, UGT1A1 and 1A9 were the main active hepatic isozymes. Besides, rats and monkeys were appropriate model animals. Moreover, dipyridamole and MK571 both could significantly inhibit M4 efflux. Gene silencing results also indicated MRP4 and BCRP were major contributors in HeLa1A1 cells. Taken together, CYPs, UGTs, MRP4 and BCRP were important determinants of CA pharmacokinetics.