DRUG METABOLISM AND DISPOSITION
·
2019
·Vol. 47
·期 8
·919-927
·
IF 3.354
Xu Mao,Jian Wang,Qian Wang,Lan Yang,Yilin Li,Hao Lin,Ying Peng,Jiang Zheng
The cytochrome P450 (P450) 1 family is an important phase I enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of Zanthoxylum nitidum (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYP1A1, 1B1, and 1A2. NC significantly inhibited CYP1A1- and 1B1-catalyzed ethoxyresorufin O-deethylation activity (IC50 = 0.28 ± 0.06 and 0.32 ± 0.02 μM, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC50 > 50 μM). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with a Ki value of 0.47 ± 0.05 μM, whereas NC caused a mixed type of inhibition on CYP1A1 with Ki and KI values of 0.14 ± 0.04 and 0.19 ± 0.09 μM, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 in CYP1A1 and Ser127 in CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol [(2-OHE2) nontoxic] and 4-hydroxyestradiol [(4-OHE2) genotoxic] generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2–induced genotoxicity.
研究领域:
药理学
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毒理学
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生物化学
·
酶学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Lanjing Li,Ru Huan,Ting Liang,Han Liu,Yao Dong,Shuang Chen,Chen Zhang,Chunshan Gui
Estradiol is the most potent and biologically active form of estrogen with glucuronide as its predominant conjugation form. Major estradiol glucuronides include estradiol-3-glucuronide (E 2 3G), estradiol-17β-glucuronide (E 2 17βG), and estradiol-3-sulfate-17β-glucuronide (E 2 3S17βG). Hepatic disposition of E 2 17βG involves basolateral uptake transporters organic anion transporting polypeptide (OATP) 1B1/1B3 and apical efflux transporters multidrug resistance-associated protein 2 (MRP2)/breast cancer resistance protein (BCRP). In addition, E 2 3G and E 2 3S17βG are substrates for MRP2/BCRP. However, whether E 2 3G and E 2 3S17βG across the basolateral membrane of hepatocytes are transporter-mediated and which transporters play the most significant roles are largely unknown. Therefore, in the present study we investigated the human hepatic uptake transporters for E 2 3G and E 2 3S17βG. Our results showed that E 2 3G and E 2 3S17βG are transported by human OATPs. Specifically, E 2 3G is a substrate for OATP1B1, 1B3, and 2B1, with K m values being of 16.0, 23.8, and 6.4 μM, respectively, and OATP2B1 possesses the highest transport efficiency. E 2 3S17βG is a substrate for OATP1B1 and 1B3, with K m values being of 0.5 and 23.7 μM, respectively, and OATP1B1 has a higher transport efficiency. At low concentrations, E 2 3G and E 2 3S17βG are selective substrates for OATP2B1 and OATP1B1, respectively. Furthermore, mutual and differential inhibition between E 2 3G/E 2 3S17βG and known OATP substrates/inhibitors has been observed. In summary, our results demonstrated that basolateral OATPs and apical MRP2/BCRP could constitute the hepatic vectorial transport of E 2 3G and E 2 3S17βG from the blood to the bile. Significance Statement This study demonstrated that OATP1B1/1B3/2B1 are hepatic uptake transporters for E 2 3G, and OATP1B1/1B3 are hepatic uptake transporters for E 2 3S17βG. At low concentrations, E 2 3G and E 2 3S17βG are selectively transported by OATP2B1 and OATP1B1, respectively. The findings in this study unveil the underlying molecular mechanisms for the hepatic disposition of estradiol glucuronides E 2 3G and E 2 3S17βG.
研究领域:
药理学
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生物化学
·
分子生物学
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生理学
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药物代谢
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Ronghao Wu,Qu Zhang,Chao Xue,Zuliang Chen
17beta-estradiol (E2) is classified as an endocrine disruptor and it poses a significant threat to the environment. Despite our previous work on the preparation of green-reduced graphene immobilized Ochrobactrum sp. FJ1(FJ1@rGO) to achieve high efficiency in removing E2, the functions of strain FJ1 and rGO, as well as their removal mechanism of E2, remain not well understood. In this study, FJ1@rGO was used to remove E2 to comprehend the removal mechanism where efficiency was found to be 93.74% after 10 days of removal compared to only rGO (43.82%). This indicated that E2 degradation was based on the integration of adsorption using rGO and biodegradation through strain FJ1, as evidenced by HPLC-UV. Additionally, results confirmed that the E2 removal process by FJ1@rGO conforms to first-order degradation kinetics and pseudo-second-order kinetics, further demonstrating the synergistic effect of physical adsorption and biodegradation. LC-Q/TOF-MS analysis identified the primary degradation products as estrone (E1), 4-OH-E1, and catechol. Combining characterization analysis, rGO facilitates the transfer of electrons between cells and E2, improving the strain's tolerance of environmental changes. Finally, the assessment of various wastewaters showed that the removal efficiency was 99.76%, 96.89%, and 78.09%, respectively. Overall, the mechanism by FJ1@rGO to remove E2 was proposed here, providing new insights into green and sustainable technology for treating E2 in wastewater.
研究领域:
环境科学
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微生物学
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DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Long Li,Jibran Iqbal,Ying Zhu,Fang Wang,Feiyu Zhang,Wanchao Chen,Ting Wu,Yiping Du
Alumina, as a support material, was loaded together with chitosan and hydroxyapatite to form chitosan/Al 2 O 3 -HA composite beads and was used for estradiol and chrysoidin removal from aqueous solution in the present work. The physicochemical properties of the beads were studied with Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectrometry (FTIR), thermogravimetric analysis (TGA) and Brunauer-Emmett-Teller (BET) surface area analysis. FTIR spectra confirmed that the chitosan was loaded successfully on Al 2 O 3 -HA, and functional groups were immobilized onto the surface of the beads after the synthesis. The adsorption condition including pH, the amount of adsorbent, initial concentration and time were evaluated during the batch experiments. Isotherm data best matched the Langmuir model and the pseudo-second-order model best described the adsorption kinetics . The maximum adsorption capacity was found to be 39.78 mg/g and 23.26 mg/g for estradiol and chrysoidine, respectively. The adsorbed estradiol and chrysoidin were completely eluted from the composite beads with the eluent of 0.1 M H 2 SO 4 /MeOH and the regenerated material was used in several cycles without deterioration in its initial performances. This study suggests that the developed composite beads have high potential for the efficient removal estradiol and chrysoidin from aqueous solution.
研究领域:
环境科学
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材料科学
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DOI
PubMed
高影响因子
Journal of Water Process Engineering
·
2024
·
IF 6.3
Xiaolin Pi,Xueni Zhang,Yue Tang,Changjiang He,Lijun Luo,Siping Ji,Fengzhi Jiang
Biochar (BC) composite photocatalysts have attracted much attention by virtue of their high efficiency in removing endocrine disruptors (EDCs). However, there has been a lack of systematic research on the mechanism and constitutive relationship of BC on photocatalysts, which has seriously impeded the development process in this field. In this study, Bi 2 WO 6 –BC 2% composite photocatalysts were prepared by microwave-assisted hydrothermal method and used for degradation of 17α-ethinylestradiol (EE2) and 17β-estradiol (E2) in conjunction with persulfate synergy (PS). The removal rate of EE2 and E2 by Bi 2 WO 6 –BC 2% was as high as 99.41 % (12 min) and 97.84 % (15 min), respectively. Systematic studies have shown that BC enhances the catalytic activity mainly through the following ways, increasing the specific surface area of the photocatalytic system, enriching the types of functional groups, enhancing the separation ability of photogenerated electron–hole pairs, and promoting the concentration of active free radicals. The results of the phytotoxicity experiments showed that compared to the EE2 or E2 pollutant solutions, the stem and root lengths of V. radiata increased by 93.63 % and 389.58 % in EE2 metabolites, and by 117.35 % and 160.38 % in E2 metabolites. Similarly, the stem and root lengths of P. vulgaris increased by 80.08 % and 174.91 % in EE2 metabolites, and by 188.92 % and 345.75 % in E2 metabolites. This work not only fills the gap in the study of the mechanism of action of BC, but also provides a green catalyst with very excellent photocatalytic efficiency and detoxification properties.
研究领域:
环境科学
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光催化技术
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毒理学
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DOI
高影响因子
AAPS PHARMSCITECH
·
2017
·Vol. 18
·期 8
·2889-2897
·
IF 2.451
Xiong Hui,Fu Jinping,Sun Hanjing,Wang Enfu,Ding Yunhui,Ren Guobin,Jing Qiufang,Ren Fuzheng
Micro-particles of 17β-estradiol (ED) were prepared with polyvinylpyrrolidone (PVP) by in situ pH-dependent solubility technique. Products were characterized using multiple instruments, and molecular interactions between ED and PVP were explored. Powder X-ray diffraction and thermal analysis revealed crystalline ED in the micro-particles is hemihydrated. PVP was also present in the micro-particles. Laser particle size analysis and scanning electron microscopy revealed thin slice morphology, which might have resulted from the influence of PVP. Moreover, the results of contact angle, specific surface area, and dynamic vapor sorption showed that the surface properties of products were improved. These physicochemical properties of the micro-particles resulted in an obvious improvement in dissolution rate. Fourier transform infrared spectroscopy and 1 H nuclear magnetic resonance revealed hydrogen bonding between ED and PVP. A method was established for the preparation of micro-particles through the addition of PVP during the reaction process.
研究领域:
药剂学
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物理化学
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DOI
高影响因子
ENVIRONMENTAL POLLUTION
·
2020
·
IF 6.793
Kai Sun,Xing Cheng,Jialin Yu,Luojian Chen,Jiajun Wei,Wenjun Chen,Jun Wang,Shunyao Li,Qingzhu Liu,Youbin Si
Estrogens, which are extensive in the eco-environments, are a category of high-toxic emerging contaminants that induce metabolic disorders and even carcinogenic risks in wildlife and humans. Here we investigate whether fungus-secreted laccase can be used as a green catalyst to eliminate a representative estrogen, 17 β -estradiol (E2). A white-rot fungus Trametes hirsuta La-7 with high laccase-productivity, was isolated from pig manure-contaminated soil. Extracellular laccase activity expressed by strain La-7 was 65.4 U·mL −1 for a 3 d inoculation under the optimal fermentation parameters. The concentrated-crude laccase from Trametes hirsuta La-7 (CC- Th Lac) was capable of effectively metabolizing E2 at pH 4–6, and the apparent pseudo first-order reaction rate constant and half-life values were respectively 0.027–0.055 min −1 and 25.86–12.67 min ( R 2 > 0.98). The mass measurement of high-resolution mass spectrometry in combination with 13 C-isotope labeling identified that the main by-products of E2 metabolism were dimers, trimers , and tetramers, which are consistent with radical-driven C–C and/or C–O–C covalent coupling pathway, involving the initial enzymatic production of phenoxy radical intermediates and then the successive oxidative-oligomerization of radical intermediates. The formation of oligomers dramatically reduced the estrogenic activity of E2. Additionally, CC- Th Lac also exhibited high-efficiency metabolism capability toward E2 in the natural water and pig manure, with more than 94.4% and 91.0% of E2 having been metabolized, respectively. These findings provide a broad prospect for the clean biotechnological applications of Trametes hirsuta La-7 in estrogen-contaminated ecosystems.
研究领域:
环境生物学
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生物化学
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生态学
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PubMed
高影响因子
Frontiers in Endocrinology
·
2024
·
IF 3.9
Chen Si-Ting,Ran Feng,Shi Wen-Wen,Liu Cheng-Kan,Wang Peng-Chao,Luo Hui-Na,Yang Zeng-Ming
Nutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as the precursor for serotonin, melatonin, and kynurenine (Kyn). The imbalance between serotonin and kynurenine pathways in Trp metabolism is closely related to inflammation and depression. This study assessed the effects of Trp deficiency on mouse early pregnancy. Embryo implantation and decidualization were analysed after female mice had been fed diets containing 0.2% Trp (for the control group), 0.062% Trp (for the low Trp group) and 0% Trp (for the Trp-free group) for two months. The uteri of the mice were collected on days 4, 5, and 8 of pregnancy. On day 8 of pregnancy, the number of implantation sites were found to be similar between the control and the low Trp groups. However, no implantation sites were detected in the Trp-free group. On day 5 of pregnancy, plane polarity- and decidualization-related molecules showed abnormal expression pattern in the Trp-free group. On day 4 of pregnancy, there was no significant difference in uterine receptivity molecules between the low-Trp group and the control group, but uterine receptivity was abnormal in the Trp-free group. At implantation sites of the Trp-free group, IDO and AHR levels were markedly elevated. This potentially increased levels of Kyn, 2-hydroxy estradiol, and 4-hydroxy estradiol to affect decidualization. Hence, Trp-free diet may impair decidualization via the IDO-KYN-AHR pathway.
研究领域:
营养学
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生殖生物学
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分子生物学
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PubMed
高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
·
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
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DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2023
·
IF 6
Yajun Zhang,Licong Jia,Wei Wang,Meng Jiang,Hongying Zhang,LingMei Niu
17β-Estradiol (E2) is a common environmental endocrine and excessive estrogen will disturb the endocrine balance of human body and lead to diseases because of its accumulation in human body. The main aim of this study is to determine the trace amount of E2 in various foods. Based on aptamer specific recognition, DNA walker molecular machine and Exonuclease III-assisted dual cycle signal amplification technology, a fluorescent aptamer sensor was constructed and applied to the detection of 17β-estradiol. Atomic force microscopy (AFM) and polyacrylamide gel electrophoresis (PAGE) were used to verify the feasibility of DNA walker participating in the reaction. Under the optimal conditions, 17β-estradiol concentration showed a good linear relationship with fluorescence in the range of 5.0 × 10 −10 –1.8 × 10 −8 M, and the detection limit was 5.6 × 10 −11 M. The fluorescent aptamer sensor established in this study has good selectivity, simple operation and good specificity, and the results of its application in the determination of milk samples are satisfactory. Research findings revealed that the E2 concentration in water and milk is less than the safe limits, indicating the foods in the market are safe and can be consumed. Though the foods are safe in present content, the health risk still exists because of continuous intake of trace E2.
研究领域:
生物化学
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环境科学
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分析化学
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DOI
高影响因子
ENVIRONMENTAL RESEARCH
·
2023
·
IF 8.3
Banghao Du,Gongduan Fan,Shangwu Yang,Jing Luo,Jiaxin Wu,Kai-Qin Xu
In this study, humic acid (HA) enhanced 17β-estradiol (17β-E2) degradation by Er 3+ -CdS/MoS 2 (ECMS) was investigated under ultrasonic and light conditions. The degradation reaction rate of 17β-E2 was increased from (14.414 ± 0.315) × 10 −3 min −1 to (122.677 ± 1.729) × 10 −3 min −1 within 90 min sonophotocatalytic (SPC) reaction with the addition of HA. The results of quenching coupled with chemical probe experiments indicated that more reactive intermediates (RIs) including reactive oxygen species (ROSs) and triplet-excited states were generated in the HA-enhanced sonophotocatalytic system. The triplet-excited states of humic acid (3 HA*), hydroxyl radical (•OH), and superoxide radical (•O 2 − ) were the dominant RIs for 17β-E2 elimination. In addition, the energy- and electron-transfer process via coexisting HA also account for 12.86% and 29.24% contributions, respectively. The quantum yields of RIs in the SPC-ECMS-HA system followed the order of 3 HA* > H 2 O 2 > 1 O 2 > •O 2 − > •OH. Moreover, the spectral and fluorescence characteristics of HA were further analyzed during the sonophotocatalytic reaction process. The study expanded new insights into the comprehension of the effects of omnipresent coexisting HA and RIs formation for the removal of 17β-E2 during the sonophotocatalytic process.
研究领域:
环境科学
·
化学
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DOI
PubMed
高影响因子
Environmental Science-Processes & Impacts
·
2019
·Vol. 22
·期 1
·197-206
·
IF 2.688
Changwei Li,Xianwang Kong,Lihua Lan,Musa Abubakar Tadda,Dezhao Liu
17β-estradiol (E2) ubiquitously exists in various water bodies with long-term endocrine-disrupting and carcinogenic impacts on wildlife even at the trace level of ng L−1. However, it remains unclear how easy-to-degrade carbon sources alter E2 biodegradation patterns. In this study, E2 biodegradation by Sphingomonas sp. MCCC 1A06484 was investigated with regard to alternative carbon sources. Results showed that the bacterium preferentially utilized glucose, sodium succinate and sodium acetate over E2. Interestingly, the presence of these preferred nutrients increased the E2 removal efficiency by 20.1%. Furthermore, a positive relation (p < 0.05) between the utilization of total organic carbon (TOC) and E2 was found. Using intracellular metabolomics by UHPLC-QTOF-MS, 11 up-regulated and 35 down-regulated metabolites (variable importance > 1, p < 0.05) were identified in the bacterium when cultivated with E2 under various carbon and nitrogen backgrounds. The E2 exposure contributed to metabolism changes of lipid, nucleotide, carbohydrate, amino acid and membrane transport, which were considered to play roles in the E2 metabolism. The up-regulated phosphatidylcholine might act as an indicator during the bacterial degradation of E2. Generally, this study contributes to an in-depth understanding of E2 biodegradation in complex environments with multiple carbon and nitrogen sources.
研究领域:
环境科学
·
微生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）