A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders

Fang, Zhong‐Ze; He, Rong‐Rong; Cao, Yun‐Feng; Tanaka, Naoki; Jiang, Changtao; Krausz, Kristopher W.; Qi, Yunpeng; Dong, Peipei; Ai, Chun-Zhi; Sun, Xiaoyu; Hong, Mo; Ge, Guang-Bo; Gonzalez, Frank J.; Ma, Xiaochi; Sun, Hongzhi

doi:10.1194/jlr.m040519

Cited by 32 publications

(21 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, endogenous substances like bile acids have been reported to exert strong inhibition potential towards several UGT isoforms. Among them, taurolithocholic acid (TLCA) exhibited the strongest inhibition towards UGT isoforms . The lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) showed strong inhibition towards UGT isoforms .…”

Section: Discussionmentioning

confidence: 99%

“…The antidiabetes drug glimepiride exhibited strong inhibition towards UGT1A6 . The herbal ingredient andrographolide exhibited highly specific inhibition towards UGT2B7 . The inhibition of UGTs’ activity by all these compounds strongly results in the disrupted metabolism of endogenous and exogenous substances.…”

Section: Discussionmentioning

confidence: 99%

“…The in vitro incubation system to evaluate the inhibition of UGTs' activity by compounds has been described in the previous literature. 14,15 In brief, the incubation system (total volume = 200 μL) contained recombinant human UGT isoforms, 5 mM UDPGA, 5 mM MgCl 2 , 50 mM Tris-HCl (pH = 7.4), and 4-MU in the absence or presence of different concentrations of various rivaroxaban or its derivatives. The incubation time used and protein concentration were previously determined to ensure the reaction rate within the linear range.…”

Section: In Vitro Incubation Mixture To Determine the Inhibitory Capamentioning

confidence: 99%

See 2 more Smart Citations

Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms

Yao¹,

Liu

et al. 2015

Chirality

Self Cite

View full text Add to dashboard Cite

Rivaroxaban is an oral direct factor Xa (FXa) inhibitor clinically used to prevent and treat thromboembolic disorders. Drug-drug interaction (DDI) exist for rivaroxaban and the inhibitors of CYP3A4/5. This study aims to investigate the inhibition of rivaroxaban and its derivatives with a chiral center towards UDP-glucuronosyltransferases (UGTs). Chemical synthesis was performed to obtain rivaroxaban derivatives with different chiral centers. UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was employed to evaluate the inhibition potential towards various UGT isoforms. A significant influence of rivaroxaban derivatives towards UGT1A3 was observed. Chiral centers produce different effects towards the effect of four pairs of rivaroxaban derivatives towards UGT1A3 activity, with stronger inhibition potential of S1 than R1, but stronger inhibition capability of R2, R3, R4 than S2, S3, and S4. Competitive inhibition of R3 and R4 towards UGT1A3 was demonstrated by Dixon and Lineweaver-Burk plots. In conclusion, the significant influence of rivaroxaban derivatives towards UGT1A3's activity was demonstrated in the present study. The chirality centers highly affected the inhibition behavior of rivaroxaban derivatives towards UGT1A3.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In Vitro Incubation Mixture To Determine the Inhibitory Capamentioning

confidence: 99%

See 1 more Smart Citation

Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms

Yao¹,

Liu

et al. 2015

Chirality

Self Cite

View full text Add to dashboard Cite

show abstract

“…IVIVE was carried out by applying (Eq. ) (Fang et al, ) as shown below:

V = V_{\max} \times ([],, S) true/ ([],, K_{s} \times ((),, 1 + ([],, I) true/ K_{i}) + ([],, S) \times ((),, 1 + ([],, I) true/ a K_{i}))

{AUC}_{i} true/ AUC = 1 + {[normalI]}_{in vivo} {true/ normalK}_{i}

…”

Section: Methodsmentioning

confidence: 99%

Inhibition of melatonin metabolism in humans induced by chemical components from herbs and effective prediction of this risk using a computational model

Wang

Huo

Tian

et al. 2016

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Biotransformation, by means of enzyme systems, shows high selectivity and efficiency and has been widely used in pharmaceutical research Nestl et al, 2011;Ge et al, 2013;Yang et al, 2013;Fang et al, 2013). It possesses the advantages of high regio-and stereo-selectivity, mild reaction conditions, and a simple operating procedure.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of alisol G by Penicillium janthinellum and the hCE2 inhibitory effects of its metabolites

Mai

Xin

Sun

et al. 2015

Phytochemistry Letters

View full text Add to dashboard Cite

A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders

Cited by 32 publications

References 34 publications

Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms

Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms

Inhibition of melatonin metabolism in humans induced by chemical components from herbs and effective prediction of this risk using a computational model

Biotransformation of alisol G by Penicillium janthinellum and the hCE2 inhibitory effects of its metabolites

Contact Info

Product

Resources

About