Chinese Journal of Natural Medicines
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2019
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IF 1.773
Yu-Xin WANG,Yi DU,Xia-Fei LIU,Fang-Xiu YANG,Xiao WU,Li TAN,Yi-Hong LU,Jing-Wei ZHANG,Fang ZHOU,Guang-Ji WANG
ABSTRACT We investigated the potential hepatoprotective effect of Radix Bupleuri (RB) by inducing acute liver injury (ALI) in an animal model using acetaminophen (APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serumaspartate transaminase (AST) and alanine transaminase (ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine (APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione (GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2E1 and CYP3A activity. Further investigation revealed the increasing of CYP2E1 and CYP3A protein was significantly inhibited in pretreatment group, while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.
研究领域:
药理学
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毒理学
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肝脏研究
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PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2017
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IF 5.099
Zheng-Hai Du,Jun Xia,Xiao-Chen Sun,Xue-Nan Li,Cong Zhang,Hua-Shan Zhao,Shi-Yong Zhu,Jin-Long Li
Di-(2-ethylhexyl)-phthalate (DEHP) is causing serious health hazard in wildlife animal and human through environment and food chain, including the effect of brain development and impacted neurobehavioral outcomes. However, DEHP exposure caused cerebellar toxicity in bird remains unclear. To evaluate DEHP-exerted potential neurotoxicity in cerebellum, male quails were exposed with 0, 250, 500 and 750 mg/kg BW/day DEHP by gavage treatment for 45 days. Neurobehavioral abnormality and cerebellar histopathological alternation were observed in DEHP-induced quails. DEHP exposure increased the contents of total Cytochrome P450s (CYPs) and Cytochrome b5 (Cyt b5) and the activities of NADPH-cytochrome c reductase (NCR) and aniline-4-hydeoxylase (AH) in quail cerebellum. The expression of nuclear xenobiotic receptors (NXRs) and the transcriptions of CYP enzyme isoforms were also influenced in cerebellum by DEHP exposure. These results suggested that DEHP exposure caused the toxic effects of quail cerebellum. DEHP exposure disrupted the cerebellar CYP enzyme system homeostasis via affecting the transcription of CYP enzyme isoforms. The cerebellar P450arom and CYP3A4 might be biomarkers in evaluating the neurotoxicity of DEHP in bird. Finally, this study provided new evidence that DEHP-induced toxic effect of quail cerebellum was associated with activating the NXRs responses and disrupting the CYP enzyme system homeostasis.
研究领域:
环境毒理学
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神经毒理学
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分子生物学
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PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2020
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IF 2.751
Xia Zhao,Xiang Xu,Xue-gui Wang,Yong Yin,Ming-yang Li,Ya-qiong Wu,Ying-hong Liu,Qing-hua Cheng,Chang-wei Gong,Li-tao Shen
Chilo suppressalis Walker (Lepidoptera: Crambidae) is a widely destructive pest occurring in rice, particularly in the rice-growing regions of Asia. In recent years, C. suppressalis has developed resistance to several insecticides because of the extensive use of insecticides. The resistance levels to four insecticides were determined among populations from different regions of Sichuan Province, China, using a drop-method bioassay. Based on LC 50 values of a laboratory susceptible strain, all field populations showed moderate level of resistance to triazophos (23.9- to 83.5-fold) and were either susceptible or had a low level of resistance to abamectin (2.1- to 5.8-fold). All field-collected populations had a low or moderate level of resistance to chlorpyrifos (1.7- to 47.1-fold) and monosultap (2.7- to 13.5-fold). The synergism experiment indicated that the resistance of the XW19 to triazophos may be associated with cytochrome P450 monooxygenases (P450s), with the highest synergistic ratio (SR) of 3.05-fold and increased ratio (IR) of 2.28-fold for piperonylbutoxide (PBO). The P450 activity of the TJ19 population was the greatest among the six field populations. Moreover, the relative expression levels of four resistance-related P450 genes were detected with qRT-PCR, and the results indicated that CYP324A12 , CYP321F3 and CYP9A68 were overexpressed in the resistant population, especially in the XW19 population (by 1.2-, 3.4 -, and 18.0-fold, respectively). In addition, the relative expression levels of CYP9A68 among the CZ19 and TJ19 populations were also enhanced 10.5- and 24.9-fold, respectively. These results suggested that CYP324A12 , CYP321F3 and CYP9A68 may be related to the resistance development of C. suppressalis to triazophos.
研究领域:
昆虫学
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害虫管理
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分子生物学
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PubMed
高影响因子
PeerJ
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2024
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IF 2.3
Nanyong Gao,Xiaoyu Xu,Feng Ye,Xin-yue Li,Chengqi Lin,Xiu-wei Shen,Jianchang Qian
Objectives To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo , when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.
研究领域:
药理学
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毒理学
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临床医学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2015
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IF 2.998
Ting Geng,Haihong Si,Danyu Kang,Yanjing Li,Wenzhe Huang,Gang Ding,Zhenzhong Wang,Yu’an Bi,Hong Zhang,Wei Xiao
Ethnopharmacological relevance Re Du Ning Injection (RDN), a traditional Chinese medicine injection, is made from the extracts of Lonicerae japonicae flos (LJF), Artemisiae annuae herba (AAH) and Gardeniae fructus (GF). Since last decade, RDN has been widely used in China for the treatment of fever, inflammation, allergy and viral infection. Aim of the study To elucidate the potential influences of RDN on the activities of four cytochrome P450 (CYP) isozymes in rats (CYP1A2, CYP2C11 , CYP2D1 and CYP3A1/2) by “cocktail method”. Materials and methods A sensitive and specific LC–MS method capable of simultaneous quantification of four substrates and their metabolites in rat plasma was developed and validated. Relative activity estimation of four isozymes was carried out by comparing plasma pharmacokinetics of substrates and their metabolites (phenacetin/ paracetamol for CYP1A2 , tolbutamide/4-hydroxytolbutamide for CYP2C11, dextromethorphan/ dextrorphan for CYP2D1 and dapsone/N-acetyl dapsone for CYP3A1/2) between control and RDN treatment groups. Results Compared with control group, RDN at different levels could increase the total amount of tolbutamide , dextromethorphan and dapsone absorbed into blood, while decrease the total amount of phenacetin absorbed into blood at low and medium dosage and increase it at high dosage. Conclusions RDN could inhibit the activities of CYP2C11, CYP2D1 and CYP3A1/2, induce the activity of CYP1A2 at low and medium dosage but inhibit it at high dosage. The results indicated that drug co-administrated with RDN may need dose adjustment.
研究领域:
药理学
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中药学
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临床医学
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2017
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IF 3.743
Wei Xie,Fangxing Yang
Although enantioselective accumulation of chiral pesticide has been reported in organisms, the mechanisms remain unclear. In this study, the effects of chiral pesticide metalaxyl on CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP2E1 and CYP3A were investigated in human hepatoma HepG2, rat hepatic H4IIE, chicken hepatic LMH and grass carp hepatic L8824 cells. Moreover, the residual concentrations and enantiomeric ratios (ERs) of metalaxyl were also detected in the medium. The results showed the responses of these CYP450s to metalaxyl were enzyme-dependent and species-dependent in the four cells. CYP1A1, CYP1A2, and CYP2B1 were induced in HepG2 cells, CYP2A1 and CYP2B1 were induced in H4IIE cells, CYP1A1 and CYP2B1 were induced in LMH cells, and CYP2B1 was induced in L8824 cells. The enantioselective residual of metalaxyl was detected in the medium and found to be species-specific. HepG2, H4IIE and LMH cells were inclined to attenuate S -metalaxyl and lead to decrease of ER of metalaxyl, while L8824 cells were inclined to remove R -metalaxyl and resulted in an inverse shift of ER. These findings suggest an enantioselective metabolism of metalaxyl in various species which is not only related with CYP450s and CYP450 enzyme-specific, but also species-specific.
研究领域:
环境科学
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毒理学
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药理学
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DOI
PubMed
高影响因子
Insects
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2021
·Vol. 12
·期 10
·926
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IF 2.769
Lulu Dai,Haiming Gao,Hui Chen
Simple SummaryThe bark beetle is the most well-known pest in coniferous trees worldwide. These insects only leave the host pine bark when they disperse to locate a new host. Determining howDendroctonus armandiovercome the trees’ terpene-based defense systems has been the key problem in the study of bark beetles. Therefore, the aim of this study was to discover the molecular mechanism of insect detoxification enzymes’ ability to confer resistance to terpenes. For this purpose, the genes of cytochrome P450s, glutathione S-transferases, and carboxylesterases were studied in beetles given diets containing terpenes. The results suggest that beetles express different genes in response to terpenoids, and the responses of multiple detoxifying enzymes indicate these insects’ adaption to their chemical environment.AbstractBark beetles overcome the toxic terpenoids produced by pine trees by both detoxifying and converting them into a pheromone system. Detoxification enzymes such as cytochrome P450s, glutathione S-transferases, and carboxylesterases are involved in the ability ofDendroctonus armandito adapt to its chemical environment. Ten genes from these three major classes of detoxification enzymes were selected to study how these enzymes helpD. armandito respond to the host defenses. The expression profile of these detoxification enzyme genes was observed in adult beetles after feeding on different types of diet. Significant differences were observed between two types of seminatural diet containing the phloem of pines, and a purely artificial diet containing five monoterpenes ((−)-α-pinene, (−)-β-pinene, (+)-3-carene, (±)-limonene, and turpentine oil) also caused differential transcript levels in the detoxification enzyme genes. The results suggest that monoterpenes enter the beetles through different routes (i.e., respiratory and digestive systems) and cause the expression of different genes in response, which might be involved in pheromone metabolism. In addition, the xenobiotic metabolism in bark beetles should be considered as a system comprising multiple detoxifying enzymes.Keywords:artificial feeding;chemical defense;Chinese white pine beetle;cytochrome P450;real-time qPCR
研究领域:
昆虫学
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分子生物学
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PubMed
高影响因子
JOURNAL OF PORPHYRINS AND PHTHALOCYANINES
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2022
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IF 1.914
Yiwen Yuan,Jianping Zhao,Jianfeng Li
Utilizing tetraphenylporphyrin (TPP), tetratolylporphyrin (TTP), tetramesitylporphyrin (TMP), and tetra- p -chlorophenylporphyrin (T p ClPP) as ligands, several five-coordinate high-spin p -toluenethiolate Manganese(II) complexes are isolated and studied by UV-vis, single-crystal X-ray and EPR spectroscopies. The crystal structures show noteworthy features including flexible axial p -toluenethiolate ligands and intramolecular C−H ⋅ ⋅ ⋅ π and π - π interactions between ligands and porphyrin planes. All four products are further studied by X-band EPR on both solid and solution states at 4 K which confirmed the S = 2/5 high-spin states. Temperature-dependent EPR and measurements with different equivalents of ligands are also reported for comparison. The work provides new references for the study of the active center of P450s and the biochemical reaction between cysteine residues and heme.
研究领域:
生物化学
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配位化学
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结构化学
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高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Hongyu Zhang,Guoshun Lin,Yifei Wang,Aihui Zheng,Hanlin Luo,Zhang Cao,Guige Hou,Yun Hou
Background Bisphenol S (BPS) is widely used in consumer products and food packaging, but its safety and potential risks have garnered increasing attention. Hydroxytyrosol (HT), a natural polyphenolic compound with potent antioxidant and anti-inflammatory activities, is yet to be investigated for its potential to reverse BPS-induced effects and the underlying mechanistic pathways. Methods The toxicological potential of BPS was assessed using the computational platform ProTox 3.0. Molecular experiments were performed to elucidate the effects of BPS on the nervous system. Protein-protein interaction networks were constructed to predict the targets of BPS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to explore the potential mechanisms of action, followed by molecular docking studies. We examined the therapeutic efficacy of HT against BPS-induced nerve damage using molecular assays and in vivo murine models. The key target identified by molecular docking was validated using RT-qPCR. Results Significant neurotoxic effects of BPS were identified using platform-based predictive analysis. The experimental results demonstrated that exposure to BPS not only reduced the viability of BV2 and HMC3 microglial and elevated intracellular reactive oxygen species (ROS) levels, but also induced a phenotypic shift in microglia toward a pro-inflammatory state, thereby may underscore its neurotoxic effects. Based on the results of the network toxicology analysis, BPS is potentially capable of exacerbating nerve damage via its modulatory effects, such as its modulation of cytochrome P450 Family 1 Subfamily A (CYP1A), like-CYP1A1, CYP1A2, and cytochrome P450 Family 2 Subfamily B6 (CYP2B6), etc. Finally, subsequent confirmation using network pharmacology and molecular docking analysis revealed that HT is capable of counteracting BPS-induced effects, and that CYP1A1 is highly likely to be a pivotal target implicated in both BPS-mediated toxicity in microglia and the therapeutic mechanisms of HT. This was further verified using RT-qPCR. Conclusion CYP1A1 is a critical mediator of BPS-induced toxicity and a potential therapeutic target of HT. These findings highlight the potential of natural compounds to mitigate environmental toxicant-induced neurological damage.
研究领域:
毒理学
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神经药理学
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环境健康
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分子生物学
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药学
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PubMed
高影响因子
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
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2019
·Vol. 85
·期 23
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IF 4.077
Bingbing Ma,Qianwen Wang,Haruo Ikeda,Chunfang Zhang,Lian-Hua Xu
Our previous study showed that CYP105D7, a substrate-promiscuous P450, catalyzes the hydroxylation of 1-deoxypentalenic acid, diclofenac, naringenin, and compactin. In this study, 14 steroid compounds were screened using recombinant Escherichia coli cells harboring genes encoding CYP105D7 and redox partners (Pdx/Pdr, RhFRED, and FdxH/FprD), and the screening identified steroid A-ring 2β- and D-ring 16β-hydroxylation activity. Wild-type CYP105D7 was able to catalyze the hydroxylation of five steroids (testosterone, progesterone, 4-androstene-3,17-dione, adrenosterone, and cortisone) with low (<10%) conversion rates. Structure-guided site-directed mutagenesis of arginine residues around the substrate entrance and active site showed that the R70A and R190A single mutants and an R70A/R190A double mutant exhibited greatly enhanced conversion rates for steroid hydroxylation. For the conversion of testosterone in particular, the R70A/R190A mutant's kcat/Km values increased 1.35-fold and the in vivo conversion rates increased significantly by almost 9-fold with high regio- and stereoselectivity. Molecular docking analysis revealed that when Arg70 and Arg190 were replaced with alanine, the volume of the substrate access and binding pocket increased 1.08-fold, which might facilitate improvement of the hydroxylation efficiency of steroids.IMPORTANCE Cytochrome P450 monooxygenases (P450s) are able to introduce oxygen atoms into nonreactive hydrocarbon compounds under mild conditions, thereby offering significant advantages compared to chemical catalysts. Promiscuous P450s with broad substrate specificity and reaction diversity have significant potential for applications in various fields, including synthetic biology. The study of the function, molecular mechanisms, and rational engineering of substrate-promiscuous P450s from microbial sources is important to fulfill this potential. Here, we present a microbial substrate-promiscuous P450, CYP105D7, which can catalyze hydroxylation of steroids. The loss of the bulky side chains of Arg70 and Arg190 in the active site and substrate entrance resulted in an up to 9-fold increase in the substrate conversion rate. These findings will support future rational and semirational engineering of P450s for applications as biocatalysts.
研究领域:
生物化学
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合成生物学
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酶工程
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.4
Lili Wu,Siyu Chen,Qiyuan Yang,Xing Li,Lingyan Liu,Shengjun Ji,Shuaiyuan Tang,Sihui Zhang,Yan Wang,Runzhi Chen,Zhikun Zhan
Emodin, a bioactive compound abundant in Chinese medicinal herbs, possesses broad therapeutic potential but raises safety concerns due to conflicting reports of hepatotoxicity. This study investigated the toxicological mechanisms underlying emodin-induced liver injury. Emodin (25-100 μM) elicited dose-dependent cytotoxicity in HepG2 cells, with the cytochrome P450 (CYP) enzymes CYP1A2 and CYP3A4 identified as the primary enzymes metabolizing emodin into hydroxylated products (M1-M3). The comparative cytotoxicity assay of emodin and its metabolites in HepG2 cells indicated that CYP-mediated metabolism functions as a critical detoxification pathway. Moreover, inhibition of CYP with 1-aminobenzotriazole (ABT, 500 μM) markedly enhanced emodin (12.5-100 μM) cytotoxicity in HepG2 cells. Similarly, ABT (50 mg/kg) markedly exacerbated emodin (400 mg/kg)-induced hepatotoxicity in mice following three weeks of co-administration. Transcriptomic profiling and validation experiments demonstrated that activation of the NF-κB/NLRP3 signaling axis contributes to emodin-induced hepatic injury. Metabolomic analyses further revealed perturbations in key pathways, including lipopolysaccharide (LPS) biosynthesis, sphingolipid metabolism, and cholesterol metabolism. Integrated multi-omics analysis identified a significant positive correlation between these metabolites (LPS, sphingosine, cholesterol) and NF-κB/NLRP3 pathway genes. These findings suggest that emodin-mediated upregulation of LPS, sphingosine, and cholesterol activates the NF-κB/NLRP3 pathway, subsequently triggering hepatic injury. Collectively, this study delineates the metabolic detoxification routes of emodin and provides mechanistic insight into its hepatotoxic potential.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Yuhan Zhao,Xiaojie Zhou,Mei Li,Xinghui Qiu
Aedes albopictus is a primary vector of arboviral diseases such as dengue fever, chikungunya fever, and Zika. The rapid development of insecticide resistance is becoming a major challenge to sustainability of insecticide-based interventions for the control of Ae. albopictus borne arboviral diseases. Understanding the molecular basis of resistance is useful for developing effective insecticide-based control action. Our recent study showed that overexpression of the AalbCYP9J26 gene was associated with insecticide resistance in field Ae. albopictus populations in Beijing, but its contribution to insecticide metabolism and resistance remains unknown. In this study, the metabolic capacity of AalbCYP9J26 towards six insecticides was examined using an enzyme system reconstituted with Escherichia coli -produced AalbCYP9J26 protein and its redox partners (AalbCPR and Aalbb5). The results showed that AalbCYP9J26 was able to metabolize temephos, malathion, propoxur, permethrin, and deltamethrin, while no significant activity against bendiocarb was observed. Moreover, the Drosophila GAL4/UAS transgenic system confirmed that enhanced expression of AalbCYP9J26 conferred increased tolerance to malathion, permethrin, deltamethrin, and propoxur. This study demonstrates that AalbCYP9J26 plays a critical role in insecticide metabolism and resistance, suggesting AalbCYP9J26 may serve as a valuable biomarker for monitoring insecticide resistance and a target for new insecticidal agents.
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