New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases

Liu, Xin; Cao, Yun‐Feng; Ran, Ruixue; Dong, Peipei; Gonzalez, Frank J.; Wu, Xue; Huang, Ting; Chen, Jianxin; Fu, Zhiwei; Li, Rongshan; Liu, Yongzhe; Sun, Hongzhi; Fang, Zhong‐Ze

doi:10.1016/j.chemosphere.2015.10.076

Cited by 18 publications

(13 citation statements)

References 19 publications

(22 reference statements)

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“…This is an important insight which can help rationalize the dearth of potent inhibitors for glycosyltransferase enzymes, despite prior in silico drug design efforts. 50, 52, 53 …”

Section: Resultsmentioning

confidence: 99%

The Stories Tryptophans Tell: Exploring Protein Dynamics of Heptosyltransferase I from Escherichia coli

et al. 2017

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Heptosyltransferase I (HepI) catalyzes the addition of L-glycero-β-D-manno-heptose onto Kdo2-Lipid A, as part of the biosynthesis of the core region of lipopolysaccharide (LPS). Gram-negative bacteria with gene knockouts of HepI have reduced virulence and enhanced susceptibility to hydrophobic antibiotics, making design of inhibitors against HepI of interest. Since HepI protein dynamics are partially rate-limiting, disruption of protein dynamics might provide a new strategy for inhibiting HepI. Discerning the global mechanism of HepI is anticipated to aid development of inhibitors of LPS biosynthesis. Herein, dynamic protein rearrangements involved in the HepI catalytic cycle were probed by combining mutagenesis with intrinsic tryptophan fluorescence and circular dichroism analyses. Using wild-type and mutant forms of HepI, multiple dynamic regions were identified via monitoring fluorescence wavelength changes. Interestingly, Trp residues (Trp199 and Trp217) in the C-terminal domain (which binds ADP-Heptose) are in a more hydrophobic environment upon ODLA binding to the N-terminal domain. These residues are adjacent to the ADP-Heptose binding site (with Trp217 in van der Waals contact with the Adenine ring of ADP-Heptose), suggesting that the two binding sites interact to report on the occupancy state of the enzyme. ODLA binding was also accompanied by a significant stabilization of HepI (heating to 95 °C fails to denature the protein when in the presence of ODLA). These results suggest that conformational rearrangements, from an induced fit model of substrate binding to HepI, are important for catalysis, and the disruption of these dynamics may serve as novel mechanism for inhibiting this and other glycosyltransferase enzymes.

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“…This is an important insight which can help rationalize the dearth of potent inhibitors for glycosyltransferase enzymes, despite prior in silico drug design efforts. 50, 52, 53 …”

Section: Resultsmentioning

confidence: 99%

The Stories Tryptophans Tell: Exploring Protein Dynamics of Heptosyltransferase I from Escherichia coli

et al. 2017

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“…4-MU was used as a nonselective probe substrate for recombinant UGTs to determine the inhibition of PAEs (Liu et al, 2016). The incubation system (Chen et al, 2017) containing 100 μM PAEs, 50 mM Tris-HCl buffer (pH 7.4) and 5 mM MgCl 2 in a total volume of 200 μL, was prepared, in which different concentrations of 4-MU (110, 1200, 110, 30, 750, 30, 30, 1000, 350, 250 and 2000 μM 4-MU) and 0.125, 0.05, 0.025, 0.05, 0.025, 0.05, 0.05, 0.25, 0.05, 0.2 and 0.5 mg/ml of UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, respectively were incubated together to ensure that the reaction rates were within the linear range.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory effects of fifteen phthalate esters in human cDNA-expressed UDP-glucuronosyltransferase supersomes

Cao

Zhu

et al. 2017

Chemosphere

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Phthalate esters (PAEs) have been extensively used in industry as plasticizers and there remains concerns about their safety. The present study aimed to determine the inhibition of phthalate esters (PAEs) on the activity of the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone was used to investigate the inhibition potentials of PAEs towards various s UGTs. PAEs exhibited no significant inhibition of UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17, and limited inhibition of UGT1A6, UGT1A7 and UGT2B4. However, UGT1A9 was strongly inhibited by PAEs. In silico docking demonstrated a significant contribution of hydrogen bonds and hydrophobic interactions contributing to the inhibition of UGT by PAEs. The K values were 15.5, 52.3, 23.6, 12.2, 5.61, 2.79, 1.07, 22.8, 0.84, 73.7, 4.51, 1.74, 0.58, 6.79, 4.93, 6.73, and 7.23 μM for BBOP-UGT1A6, BBZP-UGT1A6, BBOP-UGT1A7, BBZP-UGT1A7, DiPP-UGT1A9, DiBP-UGT1A9, DCHP-UGT1A9, DBP-UGT1A9, BBZP-UGT1A9, BBOP-UGT1A9, DMEP-UGT1A9, DPP-UGT1A9, DHP-UGT1A9, DiBP-UGT2B4, DBP-UGT2B4, DAP-UGT2B4, and BBZP-UGT2B4, respectively. In conclusion, exposure to PAEs might influence the metabolic elimination of endogenous compounds and xenobiotics through inhibiting UGTs.

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“…The evaluation of inhibition of PA and PB on UGTs' activity was performed according to the previous literatures (Tang et al , ; Liu et al , ; Zhang et al , ). In vitro incubation mixture was consisted of the following ingredients in the 50 mM of Tris‐HCl buffer (pH = 7.4): MgCl 2 (5 mM), phase II co‐factor UDPGA (5 mM), the probe substrate 4‐MU, and recombinant UGTs.…”

Section: Methodsmentioning

confidence: 99%

“…Pre‐incubated for 5 min later, UDPGA was added in the incubation mixture to initiate the glucuronidation reaction of 4‐MU. The reaction temperature, reaction time, and analytical conditions have been previously described (Tang et al , ; Liu et al , ; Zhang et al , ).…”

Section: Methodsmentioning

confidence: 99%

“…For example, indinavir and sorafenib inhibit UGT1A1‐catalyzed glucuronidation of bilirubin, resulting in the elevation of plasma concentration of bilirubin (Zucker et al , ; Peer et al , ). The inhibition of bisphenol A and phthalates on the activity of UGT isoforms has been utilized to explain the toxicity mechanism of bisphenol A and phthalates (Jiang et al , ; Liu et al , ).…”

Section: Introductionmentioning

confidence: 99%

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The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

Liu

Chen

et al. 2016

Phytotherapy Research

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Praeruptorin A (PA) and B (PB) are two important compounds isolated from Bai-hua Qian-hu and have been reported to exert multiple biochemical and pharmacological activities. The present study aims to determine the inhibition of PA and PB on the activity of important phase II drug-metabolizing enzymes uridine 5'-diphospho-glucuronosyltransferase (UGTs) isoforms. In vitro UGT incubation system was used to determine the inhibition potential of PA and PB on the activity of various UGT isoforms. In silico docking was performed to explain the inhibition difference between PA and PB towards the activity of UGT1A6. Inhibition behaviour was determined, and in vitro-in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (K ) and in vivo exposure level of PA. Praeruptorin A (100 μM) exhibited the strongest inhibition on the activity of UGT1A6 and UGT2B7, with 97.8% and 90.1% activity inhibited by 100 μM of PA, respectively. In silico docking study indicates the significant contribution of hydrogen bond interaction towards the stronger inhibition of PA than PB towards UGT1A6. Praeruptorin A noncompetitively inhibited the activity of UGT1A6 and competitively inhibited the activity of UGT2B7. The inhibition kinetic parameter (K ) of PA towards UGT1A6 and UGT2B7 was calculated to be 1.2 and 3.3 μM, respectively. The [I]/K value was calculated to be 15.8 and 5.8 for the inhibition of PA on UGT1A6 and UGT2B7, indicating high inhibition potential of PA towards these two UGT isoforms in vivo. Therefore, closely monitoring the interaction between PA and drugs mainly undergoing UGT1A6 or UGT2B7-catalyzed metabolism is very necessary. Copyright © 2016 John Wiley & Sons, Ltd.

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New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases

Cited by 18 publications

References 19 publications

The Stories Tryptophans Tell: Exploring Protein Dynamics of Heptosyltransferase I from Escherichia coli

The Stories Tryptophans Tell: Exploring Protein Dynamics of Heptosyltransferase I from Escherichia coli

Inhibitory effects of fifteen phthalate esters in human cDNA-expressed UDP-glucuronosyltransferase supersomes

The Inhibition of UDP‐Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B

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