Glucuronidation of bavachinin by human tissues and expressed UGT enzymes: Identification of UGT1A1 and UGT1A8 as the major contributing enzymes

Lv, Xia; Hou, Jie; Xia, Yangliu; Ning, Jing; He, Guiyuan; Wang, Ping; Ge, Guang-Bo; Xiu, Zhilong; Yang, Ling

doi:10.1016/j.dmpk.2015.07.001

Cited by 19 publications

(15 citation statements)

References 27 publications

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“…Hence, the metabolite was characterized as BDMC‐ O ‐glucuronide. In addition, the rates of BDMC‐ O ‐glucuronidation were altered by several UGT1A1 inhibitors , nilotinib (10 μM), protopanaxatriol (500 μM) and glycyrrhetinic acid (20 μM) (Fig. D).…”

Section: Resultsmentioning

confidence: 98%

Efflux excretion of bisdemethoxycurcumin‐O‐glucuronide in UGT1A1‐overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance‐associated proteins 1 (MRP1) as the glucuronide transporters

et al. 2018

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Bisdemethoxycurcumin (BDMC) was a natural curcuminoid with many bioactivities present in turmeric (Curcuma longa L.). However, the disposition mechanisms of BDMC via uridine 5 0 -diphospho-glucuronosyltransferase (UGT) metabolism still remain unclear. Therefore, we aimed to determine the potential efflux transporters for the excretion of BDMC-O-glucuronide. Herein, chemical inhibition assays (Ko143, MK571, dipyridamole, and leukotriene C4) and biological inhibition experiments including stable knocked-down of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRPs) transporters were both performed in a HeLa cell line stably overexpressing UGT1A1 established previously. The results indicated that Ko143 (5 and 20 μM) caused a marked reduction in excretion rate (18.4-55.6%) and elevation of intracellular BDMC-O-glucuronide (28.8-48.1%), whereas MK-571 (5 and 20 μM) resulted in a significant decrease in excretion rate (6.2-61.6%) and increase of intracellular BDMC-O-glucuronide (maximal 27.1-32.6%). Furthermore, shRNAmediated silencing of BCRP transporter led to a marked reduction in the excretion rate (21.1-36.9%) and an obvious elevation of intracellular glucuronide (24.9%). Similar results were observed when MRP1 was partially silenced. In addition, MRP3 and MRP4 silencing both displayed no obvious changes on the excretion rate and intracellular levels of glucuronide. In conclusion, chemical inhibition and gene silencing results both indicated that generated BDMC-O-glucoside were excreted primarily by the BCRP and MRP1 transporters.

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Section: Resultsmentioning

confidence: 98%

Efflux excretion of bisdemethoxycurcumin‐O‐glucuronide in UGT1A1‐overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance‐associated proteins 1 (MRP1) as the glucuronide transporters

et al. 2018

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“…Four kinetic models Michaelis-Menten equation, substrate inhibition equation, Hill equation and two-site kinetics were fitted to the data of metabolic activity vs substrate concentrations, and displayed in equations (1), (2), (3) and (4), respectively. [25][26][27][28] Meanwhile, appropriate models were selected by visual inspection of the Eadie-Hofstee plot. [24] The corresponding kinetic parameters were as follows.…”

Section: Enzyme Kinetic Evaluationmentioning

confidence: 99%

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells

Yang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters. Methods Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs. Key findings Five phase I metabolites (M1-M5) and three glucuronides (G1-G3) were identified. The CL int values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches. Conclusions CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.

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“…2), which agreed with previous studies. 19,20 Considering that intestine is the rst organ that the drugs (or natural compounds) encounter aer oral uptake, the role of intestine in in vivo metabolism of bavachinin cannot be neglected.…”

Section: Discussionmentioning

confidence: 99%

“…However, so far, UDPglucuronosyltransferase (UGT) enzymes including UGT1A1, 1A3, 1A8 and 1A10 were the main contributors responsible for the glucuronidation of bavachinin. 19,20 Furthermore, little is known about its metabolism involving in human cytochrome P450s (CYP).…”

Section: Introductionmentioning

confidence: 99%

Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin

Xing

Qin

et al. 2020

RSC Adv.

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Glucuronidation of bavachinin by human tissues and expressed UGT enzymes: Identification of UGT1A1 and UGT1A8 as the major contributing enzymes

Cited by 19 publications

References 27 publications

Efflux excretion of bisdemethoxycurcumin‐O‐glucuronide in UGT1A1‐overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance‐associated proteins 1 (MRP1) as the glucuronide transporters

Efflux excretion of bisdemethoxycurcumin‐O‐glucuronide in UGT1A1‐overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance‐associated proteins 1 (MRP1) as the glucuronide transporters

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells

Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin

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