TOXICOLOGY AND APPLIED PHARMACOLOGY
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2016
·
IF 3.847
Xia Lv,Xin-Xin Wang,Jie Hou,Zhong-Ze Fang,Jing-Jing Wu,Yun-Feng Cao,Shu-Wen Liu,Guang-Bo Ge,Ling Yang
Tolcapone and entacapone are two potent catechol- O -methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities . However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease , while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants ( K i ) of tolcapone and entacapone against bilirubin- O -glucuronidation in human liver microsomes (HLM) are determined as 0.68 μM and 30.82 μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin- O -glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.
研究领域:
药理学
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生物化学
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临床医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Environmental Chemical Engineering
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2025
·
IF 7.2
Dongting Huang,Huixin You,Lirong Chen,Yongjing Liu,Hua Li
This study extends the development of a Graphene oxide@Zirconium-based metal-organic framework@Deep eutectic solvents (GO@MOF-808@DESs) through hydrothermal self-assembly using zirconium chloride and 1,3,5-benzenetricarboxylic acid (H 3 BTC), subsequently functionalized with four carbon-tailored fatty acid-based deep eutectic solvents (DESs) via ultrasonic impregnation. Comprehensive characterization of GO@MOF-808@DES confirmed the successful surface modification via DES. A dispersive micro-solid phase extraction(D-μSPE) method was established employing GO@MOF-808@DESs as an adsorbent for efficient removal of residual entacapone (ETCP) and tolcapone (TCP) from water. Optimization of the D-μSPE method revealed optimal conditions at pH 9.0, with a sample volume of 40 mL, an adsorbent dosage of 20 mg, and an adsorption time of 60 min. Under these conditions, the method achieved a significant adsorption capacity of 86.50 ± 4.79 mg/g for ETCP and 126.21 ± 2.72 mg/g for TCP. Mechanistic investigation revealed chemically dominated adsorption kinetics through pseudo-second-order modeling and Langmuir isotherm fitting. Concurrently, density functional theory (DFT) studies demonstrated that the synergistic effect between carboxyl-mediated hydrogen bonding and hydrophobic interactions led to enhanced adsorption performance. The engineered GO@MOF-808@DESs based D-μSPE method demonstrated superior performance in removing ETCP and TCP from river water matrices, achieving 99.67 % and 99.24 %, respectively. Meanwhile, a sensitive and reliable method for trace-level monitoring of ETCP and TCP residues in environmental waters was successfully proposed, employing GO@MOF-808@DESs-based D-μSPE coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). This study presents a robust strategy for fabricating high-performance GO@MOF-808@DESs composite materials, demonstrating significant potential for practical applications.
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DOI
高影响因子
RSC Advances
·
2020
·Vol. 10
·期 39
·22966-22971
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IF 3.119
Ling Xiao,Dehui Chi,Guiju Sheng,Wenjuan Li,Penghui Lin,Sicheng Liang,Liangliang Zhu,Peipei Dong
UDP-glucuronosyltransferases (UGTs) and β-glucuronidase (GUS) catalyze entirely distinct metabolism reactions. UGTs are responsible for the glucuronidation of a variety of drugs, endogenous and environmental chemicals, whereas GUS hydrolyzes glucuronides and liberates the parent substrates. Information on the overlap of ligand selectivity between UGT and GUS is essential for exploring the pharmacological or toxicological effects of the inhibitors of these two metabolic enzymes. This study is conducted to test whether UGTs and GUS share common ligands, by investigating the inhibitory effects towards E. coli GUS by a series of UGT typical substrates and inhibitors. Results showed that three typical ligands of UGTs, including two specific substrates (estradiol and trifluoperazine, E2 and TFP) and one selective inhibitor (magnolol, Mag), can inhibit the activity of GUS. Kinetic assays indicated that all the three UGT specific chemicals displayed competitive inhibition, with Ki values of 31.4 (E2), 56.9 (TFP), and 16.6 μM (Mag). Docking studies further revealed that the three chemicals can enter the active sites of GUS by forming contacts with residues Glu-413, Trp-549, Asp-163, Tyr-472, Arg-562, or bound water. Our study indicates that ligand selectivity overlaps between UGTs and GUS, and some chemicals can act as co-inhibitors of these two metabolic enzymes. The pharmacological or toxicological effects of those co-inhibitors require further investigations.
研究领域:
药理学
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生物化学
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毒理学
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DOI
PubMed
高影响因子
Materials Today Nano
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2022
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IF 13.364
X. Cui,Y. Zhou,Y. Zheng,L. Cao,L. Gao,J. Duan,H. Yin,S. Ai
N 6 -methyladenosine (m 6 A) is the most abundant and dynamic reversible modification of mRNA in eukaryotes discovered in the mid-1970s, which is widely involved in various physiological processes. Fat mass and obesity-associated protein (FTO protein) is not only a demethylase for m 6 A, but also a carcinogenic factor for many human cancers. Therefore, it is very important to build a simple and sensitive platform for simultaneous detection of m 6 A and FTO protein. To achieve this aim, a novel photoelectrochemical biosensor was constructed with the antibody-free detection strategy of DTT mediated –SH functionalization of m 6 A triggered by FTO protein catalyzed m 6 A oxidation . To achieve high detection sensitivity, CdS/Bi 2 MoO 6 /MoSe 2 system with matched energy gap was employed as photoactive material. To achieve high detection selectivity , the –CH 3 of m 6 A in the captured RNA sequence (m 6 A RNA) on the electrode surface was oxidized by FTO protein to form hydroxymethyl, followed with the covalent reaction of DTT with hydroxymethyl, making the labeling of m 6 A with –SH. Finally, a CdS nanoparticle was modified on the electrode through the specific covalent reaction between –SH and Cd, achieving the improvement of the photocurrent with the matched energy band . Under the optimal experimental conditions, the biosensor showed linear range from 0.001 to 50 nM and 0.0005–500 μg/L with the detection limit of 0.37 pM and 0.034 ng/L (S/N = 3) for m 6 A RNA and FTO protein, respectively. The applicability of the developed method was assessed by investigating the effect of entacapone on FTO protein activity.
研究领域:
生物化学
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分析化学
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生物技术
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癌症研究
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DOI
高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
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2022
·
IF 5.011
Liangliang Zhu,Hui Lv,Ling Xiao,Yanyao Hou,Wenjuan Li,Guangbo Ge,Chunzhi Ai
β-estradiol (β-E2) and α-estradiol (α-E2) act as an endo- and an exon-estrogen in humans, respectively. There is a structural variation in C17-OH configuration of the two estrogens. UDP-glucuronosyltransferases (UGT) are responsible for termination of activities of a variety of endogenous hormones, clinical drugs, and environmental toxicants. The current study was conducted to investigate the effects of the two estrogens towards catalytic activities of UGTs. It was found that β-E2 could decrease activities of UGT1A9 , − 2B4 and − 2B7, with K i values of a few micro-molars. β-E2 could additionally accelerate the activity of UGT2B17 via promoting enzyme-substrate binding and increasing the turn over number . Comparatively, α-E2 displayed much stronger inhibitory potentials towards UGT2B7 and − 2B4, but showed little influence to UGT1A9 and − 2B17. The K i values for inhibition of UGT2B7 in glucuronidation of different substrates by α-E2 were in a nanomolar range that is only about 1/100–1/50 of β-E2. UGT2B7 structural model was fatherly constructed to explore the mechanism underlying dramatically different inhibition selectivity of the two estrogens. Compared to β-E2, α-E2 formed more hydrophobic and hydrogen-bonded interactions with the residues in the active pocket. It is concluded that the configuration of E2–17-OH determines the inhibitory potentials towards UGTs. The results are useful in better understanding ligand selectivity of UGTs, as well as in further development of α-E2 in health protection.
研究领域:
药理学
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生物化学
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分子生物学
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内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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