CHEMISTRY AND ECOLOGY
·
2017
·
IF 1.463
Haixia Zhan,Jinping Zhang,Zhu Chen,Yongjie Huang,Teija Ruuhola,Shiyong Yang
Cadmium (Cd) is a toxic non-essential element accumulated easily in living organisms due to its non-biodegradable nature. A slight increase in Cd levels will threaten the health of terrestrial and aquatic organisms. Therefore, Cd contamination and its effects on the ecosystems and organisms have become a major topic of eco-toxicological research. The present study investigated the eco-toxicological effects of Cd-supplemented diet on some life history traits and specific enzyme activities of carboxylesterase (CarE), glutathione S-transferase (GST), acetylcholinesterase (AChE) and cytochrome P450 monooxygenases (P450s) in the cotton bollworm, Helicoverpa armigera. The results showed that Cd significantly decreased larval survival, pupation and emergence, and reduced body mass of the sixth instar larvae, pupae, adult moths and female fecundity. Cd-supplemented diet also delayed the development of larvae and pupae and shortened the life span of the cotton bollworm moth. In addition, dietary Cd inhibited the activities of GST, CarE and P450, but increased AChE activity of the sixth instar larvae. We concluded that life history traits and metabolic enzymes are sensitive to Cd stress in the cotton bollworm. These parameters are potential biomarkers for monitoring environmental stress in Lepidopteran insect pests.
研究领域:
生态毒理学
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昆虫学
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环境科学
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产品关联
DOI
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2019
·
IF 2.983
Shuai Ji,Xian Shao,Zhen-yu Su,Lei Ji,Yu-jie Wang,Yun-su Ma,Lu Zhao,Yan Du,Meng-zhe Guo,Dao-quan Tang
Fufang Danshen Dripping Pill (FDDP) and Clopidogrel Bisulfate Tablet (CBT) are usually combined for treatment of coronary artery diseases in clinical. To investigate the pharmacokinetic interaction between FDDP and CBT after oral administration of FDDP, CBT and their combination in rats, a novel LC–MS method with segmented scan modes (multiple reaction monitoring and selected ion monitoring) and polarity (positive and negative ionization) was developed. Clopidogrel and the main active ingredients of FDDP, with different chemical and ionization properties, were simultaneously quantified in plasma in a single run. The method was validated in terms of specificity, linearity, precision, accuracy, recovery, matrix effect and stability. As a result, co-administration of FDDP and CBT significantly altered the pharmacokinetic parameters of danshensu, ginsenoside Rb1, dihydrotanshinone I, tanshinone I and tanshinone IIA of FDDP, as well as clopidogrel. Mechanism studies suggested that induction of liver cytochrome P450 isozymes CYP2C11 and CYP3A1 by co-administration, as well as inhibition of carboxyl esterase 1, was partly responsible for FDDP-CBT pharmacokinetic interactions. The developed LC–MS method could be used to simultaneously quantify different types of in vivo analytes in a single run, and the results could be used for clinical medication guidance of FDDP and CBT.
研究领域:
药理学
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分析化学
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药学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Chao Wang,Shuyi Zhang,Zijin Shao,Peijie Sun,Jiran Zhang,Shaoping Zhang,Jian Kong,Hong Zhi,Li Li,Mingshu Li,Jie Yu,Zhenming Liu,Xiaobo Lu,Hui Peng,Song Tang
Bisphenol A (BPA) is a well-known endocrine-disrupting pollutant that poses significant environmental challenges globally. However, the toxicity of nitro-BPA (NBPA), the primary transformation product of BPA, remains poorly understood. This study employs a multi-omics approach, integrating in silico and bioinformatics analyses, to investigate and compare the male reproductive toxicity of BPA and NBPA in male zebrafish exposed to environmentally relevant concentrations. After 21 days of exposure, we observed a significant increase in cumulative egg production over five days in the NBPA 200 nM group compared to pre-exposure levels. Conversely, the gonadosomatic index of NBPA 200 nM group was significantly reduced by approximately 41.65 %. Our findings indicate that the activation of ESRRγ and inhibition of NR5A2 are critical molecular initiating events linked to male reproductive toxicity. Additionally, both BPA and NBPA were found to disrupt several key events within the steroid hormone biosynthesis pathway. This disruption includes the downregulation of genes encoding cytochrome P450 (CYP450) and hydroxysteroid dehydrogenase enzymes, as well as alterations in the levels of steroid hormones such as cholesterol and 25-hydroxycholesterol. Our study identifies biomolecular targets of BPA and NBPA at environmentally relevant concentrations that induce reproductive toxicity, enhancing our understanding of NBPA toxicity and are anticipated to inform the development of effective mitigation strategies.
研究领域:
环境科学
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毒理学
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分子生物学
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水生生态学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Tengfei Xiong,Mingyue Yu,Jiang Zhu,Kai Tian,Mei Li,Xinghui Qiu
The oriental tobacco budworm Helicoverpa assulta (Lepidoptera: Noctuidae) is a specialist pest that may cause serious damages to important crops such as chili pepper and tobacco. Various man-made insecticides have been applied to control the infestation of this pest. To understand how this pest copes with insecticides, it is required to identify key players involved in insecticide transformation. In this study, a P450 gene of CYP6B subfamily was identified in the oriental tobacco budworm, and its expression pattern was revealed . Moreover, the activities of HassCYP6B6 against 12 insecticides were explored using recombinant enzymes produced in the facile Escherichia coli . Data from metabolic experiments showed that HassCYP6B6 was able to metabolize conventional insecticides including organophosporates (diazinon, malathion, phoxim), carbamate propoxur, and pyrethroid esfenvalerate, while no significant metabolism was observed towards new-type pesticides such as neonicotinoids (acetamiprid, imidacloprid), diamides (chlorantraniliprole, cyantraniliprole), macrocyclic lactone (emamectin benzoate, ivermectin), and metaflumizone. Structures of metabolites were proposed based on mass spectrometry analyses. The results demonstrate that HassCYP6B6 plays important roles in the transformation of multiple insecticides via substrate-dependent catalytic mechanisms including dehydrogenation, hydroxylation and oxidative desulfurization. The findings have important applied implications for the usage of insecticides.
研究领域:
昆虫学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
BIORESOURCE TECHNOLOGY
·
2025
·
IF 9
Shiye Zhu,Jiale Zhang,Anwei Chen,Youzheng Chai,Jianhua Zeng,Gen Lu,Ma Bai,Jihai Shao,Liang Peng,Si Luo
Agricultural expansion has led to the accumulation of neonicotinoid pesticides in water and soil, which are habitats for widespread cyanobacteria. However, the cyanobacteria-neonicotinoids interaction mechanisms remain unclear. This study first explores Thiamethoxam (THX) biodegradation by Nostoc sp. PCC7120, elucidating cytochrome P450 (CYP450)-mediated THX metabolism. Nostoc sp. PCC7120 could remove THX completely within 6 days mainly via biodegradation (75 %). While THX stimulates cell growth, evidence (damaged thylakoid membranes, lowered electron transfer efficiency, reduced photosynthetic pigments, and altered key gene expression) shows it disrupts photosynthesis. Furthermore, THX degradation involved ring opening, nitrate reduction, de-chlorination, and N -dealkylation; molecular dynamics simulations revealed THX stably binding (32.38 kcal/mol) to CYP450′s active site and primary degradation via hydroxylation and de-chlorination. Ecotoxicity assessments show desmethyl and urea metabolites are more toxic to non-target organisms and humans than the parent compound. This study elucidates THX removal mechanisms and environmental fate, highlighting cyanobacteria’s potential in bioremediation for agricultural wastewater.
研究领域:
环境科学
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微生物学
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生态毒理学
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生物技术
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农业化学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2019
·Vol. 47
·期 8
·794-801
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IF 3.354
Hongwei Yao,Ruifeng Bai,Tianming Ren,Yani Wang,Jingkai Gu,Yingjie Guo
Clopidogrel (Clop), a thienopyridine antiplatelet prodrug, is metabolized by cytochrome P450s (CYPs) to an active metabolite, Clop-AM, and hydrolyzed by carboxylesterase (CES)1 to the inactive Clop-acid. Patients with type 2 diabetes (T2DM) tend to have a poor response to Clop due to reduced generation of Clop-AM. Whether a similar response occurs in the Zucker diabetic fatty (ZDF) rat, a commonly used animal model of T2DM, has not been explored. In this work, we compared ZDF and control rats for hepatic CES1- and CYP-mediated Clop metabolism; pharmacokinetics of Clop, Clop-AM, and Clop-acid; and the antiplatelet efficacy of Clop. In contrast to clinical findings, Clop-treated ZDF rats displayed significantly less (50%) maximum platelet aggregation at 4 hours than control rats; the enhanced efficacy was accompanied by higher formation of Clop-AM and lower formation of Clop-acid. In vitro studies showed that hepatic levels of CES1 protein and activity and Ces1e mRNA were significantly lower in ZDF than in control rats, as were the mRNA levels of CYP2B1/2, CYP2C11, and CYP3A2, and levels of CYP2B6-, CYP2C19-, and CYP3A4-related proteins and enzymatic activities in liver microsomes of ZDF rats. Interestingly, liver microsomes of ZDF rats produced higher levels of Clop-AM than that of control rats despite their lower CYP levels, although the addition of fluoride ion, an esterase inhibitor, enhanced Clop-AM formation in control rats more than in ZDF rats. These results suggest that the reduction in CES1-based Clop inactivation indirectly enhances Clop efficacy in ZDF rats by making more Clop available for CYP-mediated Clop-AM formation.
研究领域:
药理学
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糖尿病研究
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代谢
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药物动力学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2016
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IF 3.025
Hui Wang,Yukun Feng,Qian Wang,Xiucai Guo,Wenlin Huang,Ying Peng,Jiang Zheng
Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR-induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR-induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Zilu Wang,Minghao Jiang,Fan Yin,Mali Wang,Jinfang Jiang,Min Liao,Haiqun Cao,Ning Zhao
Alopecurus aequalis Sobol. is a predominant grass weed in Chinese winter wheat fields, posing a substantial threat to crop production owing to its escalating herbicide resistance. This study documented the initial instance of an A. aequalis population (AHFT-3) manifesting resistance to multiple herbicides targeting four distinct sites: acetyl-CoA carboxylase (ACCase), acetolactate synthase, photosystem II, and 1-deoxy-d-xylulose-5-phosphate synthase. AHFT-3 carried an Asp-to-Gly mutation at codon 2078 of ACCase, with no mutations in the remaining three herbicide target genes, and exhibited no overexpression of any target gene. Compared with the susceptible population AHFY-3, AHFT-3 metabolized mesosulfuron-methyl, isoproturon, and bixlozone faster. The inhibition and comparison of herbicide-detoxifying enzyme activities indicated the participation of cytochrome P450s in the resistance to all four herbicides, with glutathione S-transferases specifically linked to mesosulfuron-methyl. Three CYP72As and a Tau class glutathione S-transferase, markedly upregulated in resistant plants, potentially played pivotal roles in the multiple-herbicide-resistance phenotype.
研究领域:
植物科学
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杂草科学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2024
·Vol. 25
·期 10
·754-768
·
IF 2.1
Xiaoyun Liu,Dafang Zhong,Chongzhuang Tang,Xiaofeng Xu,Hong Lan,Xingxing Diao
Background BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations. Objectives This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372. Methods The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS). Results BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree. Conclusion This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.
研究领域:
药理学
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药物代谢
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肿瘤学
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生物化学
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临床药理学
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分析化学
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毒理学
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分子生物学
✓ 已验证
DOI
高影响因子
JOURNAL OF TOXICOLOGICAL SCIENCES
·
2019
·
IF 1.732
Nana Long,Huaqiao Tang,Lin Lin,Jianlong Li,Lijuan Guo,Fenghui Sun,Min Dai
Methicillin-resistant Staphylococcus aureus (MRSA) leads to serious infections, but it is not known whether it changes the expression of kidney drug metabolizing enzymes during infection. The mice were infected with different doses of MRSA and the oxidative stress and inflammation levels in the kidney were examined. The mRNA expression and activity of cytochrome P450 enzyme was analysed. Mice infected with high levels of MRSA showed a decrease in renal antioxidant capability and an elevated level of oxidative metabolites, which was accompanied by the release of inflammatory cytokines. The levels of interleukin 1β, tumour necrosis factor alpha, and macrophage inflammatory protein-1α were significantly increased along with the levels of nitric oxide and malondialdehyde. On day 7, mRNA expression of Cyp1a2, 2d22, and 3a11 were decreased by the high level of MRSA, but the low level of MRSA increased their expressions. Cyp2e1 mRNA expression was increased by MRSA in the kidney of mice. High dose of MRSA infection increased the oxidative stress and inflammatory response in mouse kidney, leading to the decrease in the expression of renal drug-metabolizing enzymes and no recovery within 7 days.
研究领域:
药理学
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微生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2014
·
IF 2.982
Qi Shen,Minjuan Zuo,Li Ma,Ye Tian,Lu Wang,Huidi Jiang,Quan Zhou,Hui Zhou,Lushan Yu,Su Zeng
Neferine is a bisbenzylisoquinoline alkaloid isolated from the seed embryos of Nelumbo nucifera Gaertn (Lotus) with various potent pharmacological effects. Recently, neferine has attracted attention for its anti-tumor activities. Our study explored its metabolism and cytotoxicity mechanism. Approaches using chemical inhibitors and recombinant human enzymes to characterize the involved enzymes and kinetic studies indicated that the demethylation of neferine by cytochrome P450 (CYP) 2D6 and CYP3A4 fitted a biphasic kinetic profile. Glutathione (GSH) was used as a trapping agent to identify reactive metabolites of neferine, and four novel GSH conjugates were detected with [M+H] + ions at m / z 902.4, 916.2, 916.1, and 930.4. Based on its structure containing para -methylene phenol and results from a product ion scan, GSH tends to conjugate with C9’ after undergoing oxidative metabolism to form the binding site predominated by CYP3A4. Furthermore, the addition of recombinant human GSTA1, GSTT1, and GSTP1 had little effect on the production of the GSH conjugates. In a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, combined with the GSH modulators l -buthionine sulfoximine or N -acetyl- l -cysteine, neferine treatment of MDCK-hCYP3A4 and HepG2 cells revealed that CYP3A4 expression and cellular GSH content could cause an EC 50 shift. Metabolic activation mediated by CYP3A4 and GSH depletion significantly enhanced neferine-induced cytotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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肿瘤学
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酶学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2020
·
IF 4.192
Yi Zhao,Jia Lin,Milton Talukder,Shi-Yong Zhu,Mu-Zi Li,Hao-Ran Wang,Jin-Long Li
Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer to improve product flexibility and workability. Lycopene (LYC) is a natural compound and has promising preventive potentials, especially antireproductive toxicity, but the specific underlying mechanism is yet to be fully defined. Our study investigated the effect of LYC on DEHP-induced spermatogenesis disorders. Male ICR mice were treated with DEHP (500 or 1000 mg/kg BW/day) and/or LYC (5 mg/kg BW/day) for 28 days. Our results indicated that LYC could relieve the DEHP-induced injury of seminiferous tubules and spermatogenic cells, swelling of endoplasmic reticulum (ER), and an increase of mitochondria. LYC prevented increased levels of nuclear damage to DNA and the deformity rate and decreased values of sperm motility, number, and density. Moreover, LYC treatment decreased DEHP-induced nuclear accumulation of aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT), and the expressions of their downstream target genes such as cytochrome P450-dependent monooxygenases (CYP) 1A1, 1A2, and 1B1 were markedly reduced to normal in the LYC treatment group. Our study showed that LYC can prevent DEHP-induced spermatogenic disorders via an AHR/ARNT signaling system. This study provided new evidence of AHR as a target for LYC, which can prevent DEHP-induced toxicity.
研究领域:
毒理学
·
生殖生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）