JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Yan He,Zihao Cheng,Jingyu Zhang,Yu Chen,Guode Zhao,Hong Tang,Yufen Liao,Tingmin Ye,Ying Peng,Weiwei Li,Jiang Zheng
Myristicin (MYR) mainly occurs in nutmeg and belongs to alkoxy-substituted allylbenzenes, a class of potentially toxic natural chemicals. RNA interaction with MYR metabolites in vitro and in vivo has been investigated in order to gain a better understanding of MYR toxicities. We detected two guanosine adducts (GA1 and GA2), two adenosine adducts (AA1 and AA2), and two cytosine adducts (CA1 and CA2) by LC-MS/MS analysis of total RNA extracts from cultured primary mouse hepatocytes and liver tissues of mice after exposure to MYR. An order of nucleoside adductions was found to be GAs > AAs > CAs, and the result of density functional theory calculations was in agreement with that detected by the LC-MS/MS-based approach. In vitro and in vivo studies have shown that MYR was oxidized by cytochrome P450 enzymes to 1′-hydroxyl and 3′-hydroxyl metabolites, which were then sulfated by sulfotransferases (SULTs) to form sulfate esters. The resulting sulfates would react with the nucleosides by SN1 and/or SN2 reactions, resulting in RNA adduction. The modification may alter the biochemical properties of RNA and disrupt RNA functions, perhaps partially contributing to the toxicities of MYR.
研究领域:
毒理学
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药理学
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分子生物学
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分析化学
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PubMed
高影响因子
AAPS Journal
·
2013
·Vol. 16
·期 1
·101-113
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IF 4.386
Qiao Xue,Ji Shuai,Yu Si-wang,Lin Xiong-hao,Jin Hong-wei,Duan Yao-kai,Zhang Liang-ren,Guo De-an,Ye Min
Licorice has been shown to affect the activities of several cytochrome P450 enzymes. This study aims to identify the key constituents in licorice which may affect these activities. Bioactivity assay was combined with metabolic profiling to identify these compounds in several complex licorice extracts. Firstly, the inhibition potencies of 40 pure licorice compounds were tested using an liquid chromatography/tandem mass spectrometry cocktail method. Significant inhibitors of human P450 isozymes 1A2, 2C9, 2C19, 2D6, and 3A4 were then selected for examination of their structural features by molecular docking to determine their molecular interaction with several P450 isozymes. Based on the present in vitro inhibition findings, along with our previous in vivo metabolic studies and the prevalence of individual compounds in licorice extract, we identified several licorice constituents, viz ., liquiritigenin, isoliquiritigenin, together with seven isoprenylated flavonoids and arylcoumarins, which could be key components responsible for the herb–drug interaction between cytochrome P450 and licorice. In addition, hydrophilic flavonoid glycosides and saponins may be converted into these P450 inhibitors in vivo . These studies represent a comprehensive examination of the potential effects of licorice components on the metabolic activities of P450 enzymes.
研究领域:
药理学
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分析化学
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生物化学
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药学
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PubMed
高影响因子
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
·
2023
·Vol. 120
·期 37
·e2308685120
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IF 11.1
Yu Shi,Qingqing Liu,Wenjie Lu,Jing Yuan,Yihua Yang,John Oakeshott,Yidong Wu
Here, we provide mechanistic support for the involvement of the CYP9A subfamily of cytochrome P450 monooxygenases in the detoxification of host plant defense compounds and chemical insecticides in Spodoptera exigua and Spodoptera frugiperda. Our comparative genomics shows that a large cluster of CYP9A genes occurs in the two species but with significant differences in its contents, including several species-specific duplicates and substantial sequence divergence, both between orthologs and between duplicates. Bioassays of CRISPR-Cas9 knockouts of the clusters show that, collectively, the CYP9As can detoxify two furanocoumarin plant defense compounds (imperatorin and xanthotoxin) and insecticides representing three different chemotypes (pyrethroids, avermectins, and oxadiazines). However, in vitro metabolic assays of heterologously expressed products of individual genes show several differences between the species in the particular CYP9As with activities against these compounds. We also find that the clusters show tight genetic linkage with high levels of pyrethroid resistance in field strains of the two species. We propose that their divergent amplifications of the CYP9A subfamily have not only contributed to the development of the broad host ranges of these species over long evolutionary timeframes but also supplied them with diverse genetic options for evolving resistance to chemical insecticides in the very recent past.
研究领域:
昆虫学
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分子生物学
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基因组学
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毒理学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Jie Li,Jikai Gao,Jiaying Ai,Ziyang Yin,Fuping Lu,Hui-Min Qin,Shuhong Mao
17α-Hydroxyprogesterone (17α-OH-PROG) is an important intermediate with a wide range of applications in the pharmaceutical industry. Strategies based on efficient electron transfer and cofactor regeneration were used for the production of 17α-OH-PROG. Here, CYP260A1, Fpr and Adx were expressed using a double plasmid system, resulting in higher biotransformation efficiency. Further optimization of reaction conditions and addition of polymyxin B increased the production of 17α-OH-PROG from 12.52 mg/L to 102.37 mg/L after 12 h of biotransformation. To avoid the addition of external 5-aminolevulinic acid (ALA) as a heme precursor for the P450 enzyme, a modified C5 pathway was introduced into the engineered strain, further reducing the overall process cost. The resulting whole-cell biocatalyst achieved the highest biotransformation yield of 17α-OH-PROG reported to date, offering a promising strategy for commercial application of P450 enzymes in industrial production of hydroxylated intermediates.
研究领域:
生物化学
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制药工程
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合成生物学
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PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2013
·
IF 2.111
Wang Hongchun,Li Jun,Lv Bo,Lou Yuanlai,Dong Liyao
Herbicide resistance or tolerance in weeds mediated by cytochrome P450 monooxygenase is a considerable problem. However, cytochrome P450 mediated resistance or tolerance in weeds was less studied. Thus, in this work, the role of the cytochrome P450 monooxygenase in the different responses of Poa annua and Alopecurus aequalis to fenoxaprop-P-ethyl was studied. We found that the effect of fenoxaprop-P-ethyl could be synergized by piperonyl butoxide (PBO) in P. annua , but not by malathion. After being treated with fenoxaprop-P-ethyl (containing mefenpyr-diethyl), the contents of cytochrome P450 and cytochrome b 5 in P. annua increased significantly compared to plants treated with mefenpyr-diethyl only or untreated plants. However, the increase was less in A. aequalis , which was susceptible to fenoxaprop-P-ethyl. The activities of ρ-nitroanisole O-demethylase (PNOD), ethoxyresorufin O-deethylase (EROD), ethoxycoumarin oxidase (ECOD) and NADPH-dependent cytochrome P450 reductase mediated by cytochrome P450 monooxygenase increased in P. annua after treatment with fenoxaprop-P-ethyl, especially the activities of ECOD and cytochrome P450 reductase. Besides this, cytochrome P450 monooxygenase activity toward fenoxaprop-P-ethyl in P. annua increased significantly compared to untreated or treated with mefenpyr-diethyl plants and treated or untreated A. aequalis . Cytochrome P450 monooxygenase may play an important role in the different responses to fenoxaprop-P-ethyl in P. annua and A. aequalis .
研究领域:
植物学
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农学
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分子生物学
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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Shuaishuai Chen,Weiyu Guo,Huan Liu,Jiang Zheng,Dingyan Lu,Jia Sun,Chun Li,Chunhua Liu,Yonglin Wang,Yong Huang,Wen Liu,Yongjun Li,Ting Liu
Psoralen and isopsoralen are the major components responsible for Psoraleae Fructus-induced hepatotoxicity. This study explored the role of metabolic activation by cytochrome P450 (CYP) enzymes in psoralen- and isopsoralen-induced cytotoxicity and its potential mechanisms. Inhibitors of CYP1A2 , 2C9, 2C19, 2D6, 2E1, and 3A4 were used to screen specific CYP enzymes responsible for the metabolic activation of psoralen and isopsoralen in mouse primary hepatocytes, which was verified using the corresponding transfected cell lines. Network toxicology and transcriptome analyses were performed to explore the mechanisms underlying toxicity. Psoralen and isopsoralen decreased the viability of mouse primary hepatocytes, whereas the inhibition of CYP2C9 , 2C19, 2D6, and 2E1 significantly increased their viability. Psoralen-induced cytotoxicity was significantly enhanced by the overexpression of CYP2C19 in Chinese hamster ovary cells, whereas the overexpression of the above CYP enzymes did not affect the cytotoxicity of isopsoralen. Psoralen- and isopsoralen-induced cytotoxic effects were associated with putative core targets (i.e., Fn1 , Thbs1 , and Tlr2) and multiple signaling pathways (e.g., PI3K-Akt, MAPK , and TNF pathways). Our results demonstrate that the metabolic activation of psoralen and isopsoralen is mediated by CYP enzymes, thereby regulating multiple core targets and signaling pathways and resulting in cytotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Yun Huang,Junyue Zheng,Peizhuo Wu,Yu Zhang,Lihong Qiu
Cytochrome P450 CYP6B7 has previously been proved to be associated with fenvalerate-resistance in Helicoverpa armigera. Here, how CYP6B7 is regulated and involved in the resistance of H. armigera is studied. Seven base differences (M1–M7) were found in CYP6B7 promoter between a fenvalerate-resistant (HDTJFR) and a susceptible (HDTJ) strain of H. armigera. M1–M7 sites in HDTJFR were mutated into the corresponding base in HDTJ, and pGL3-CYP6B7 reporter genes with different mutation sites were constructed. Fenvalerate-induced activities of reporter genes mutated at M3, M4, and M7 sites were significantly reduced. Transcription factors Ubx and Br, whose binding sites contain M3 and M7, respectively, were overexpressed in HDTJFR. Knockdown of Ubx and Br results in significant expression inhibition of CYP6B7 and other resistance-related P450 genes, and increase of sensitivity of H. armigera to fenvalerate. These results indicate that Ubx and Br regulate the expression of CYP6B7 to mediate the fenvalerate-resistance in H. armigera.
研究领域:
昆虫学
·
分子生物学
·
遗传学
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DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
·
2022
·Vol. 78
·期 6
·2240-2249
·
IF 4.462
Tan Dai,Zhiwen Wang,Xingkai Cheng,Huige Gao,Li Liang,Pengfei Liu,Xili Liu
BACKGROUND Fungicide resistance has become a serious problem for different mode of action groups except for uncouplers, which makes their resistance mechanism a hot topic, which until now, has not been well clarified. SYP-14288, a newly developed diarylamine fungicide modeled on fluazinam, has shown good toxicity to both oomycete and fungus by the action of uncoupling. In this research, the resistance of Phytophthora capsici to SYP-14288 was studied to clarify the resistance mechanism of uncouplers. RESULTS The toxicity tests of resistant strains against SYP-14288 showed multidrug resistance. The high-performance liquid chromatography (HPLC) results showed that resistant strains could efflux the fungicide, and this ability could be inhibited by the efflux pump inhibitor amitriptyline. The target protein of amitriptyline is P-glycoprotein (P-gp), which was overexpressed in resistant strains. Three products of nitrate reduction of SYP-14288 were detected and determined by HPLC-Q-TOF. Eight cytochrome P450 monooxygenase (P450) proteins were differentially involved in the reduction reaction. CONCLUSION Both fungicide efflux and detoxification metabolism were involved in the resistance mechanisms of P. capsici to SYP-14288. © 2022 Society of Chemical Industry.
研究领域:
植物病理学
·
分子生物学
·
杀菌剂科学
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PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2022
·Vol. 19
·期 5
·e202200177
·
IF 2.745
Susu Lin,Bingbing Ma,Qilin Gao,Jian Yang,Gang Lai,Runhao Lin,Bingxian Yang,Bing-Nan Han,Lian-Hua Xu
Cytochrome P450 enzymes (CYPs or P450s) are ubiquitous heme-dependent enzymes that catalyze the monooxygenation of non-activated C−H bonds to modify the structure of the substrate. In this study, we heterologously expressed CYP107X1 from Streptomyces avermitilis and conducted in vitro substrate screening using the alternative redox partners putidaredoxin and putidaredoxin reductase. CYP107X1 catalyzed the 16α-hydroxylation of progesterone with regio- and stereoselectivity. The spectroscopic analyses showed that CYP107X1 bound progesterone with a relatively high K d value of 65.3±38.9 μM. The K m and k cat values for progesterone were estimated to be 47.7±12.0 μM and 0.30 min −1 , respectively. Furthermore, a crystal structure was obtained of CYP107X1 bound with glycerol from the buffer solution. Interestingly, a conserved threonine was replaced with asparagine in CYP107X1, indicating that it may adopt an unnatural proton transfer process and play a crucial role in its catalytic activity.
研究领域:
生物化学
·
酶学
·
结构生物学
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
He Liu,Zixia Hu,Ningning Han,Yi Yang,Guode Zhao,Mengdie Su,Yue Zhang,Weiwei Li,Ying Peng,Jiang Zheng
Metaxalone (MTX) is a central nervous system (CNS) depressant used for the treatment of acute skeletal muscle pain . Several cases of fatal overdose deaths in the clinical use of MTX, along with the presence of ischemic hepatitis in deceased patients, have been documented. The present study aimed to investigate the metabolic activation of MTX and to define the possible correlation between the metabolic activation and cytotoxicity of MTX. An oxidative metabolite (M1) and a GSH conjugate (M2) were observed in S9 fraction incubations as well as in rat primary hepatocyte culture after exposure to MTX. M1 and M2 were also observed in bile of MTX-treated rats. CYP2A6 was found to dominate the oxidation of MTX. Both methoxsalen (MTS, a CYP2A6 inhibitor) and 2,6-dichloro-4-nitrophenol (DCNP, a sulfotransferase inhibitor) dramatically decreased the formation of M2. Pre-treatment of primary hepatocytes with DCNP or MTS significantly decreased the susceptibility to the cytotoxicity of MTX.
研究领域:
药理学
·
毒理学
·
药物代谢
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2016
·Vol. 31
·期 7
·e3905
·
IF 1.729
Danyu Kang,Ting Geng,Yuanpei Lian,Yanjing Li,Gang Ding,Wenzhe Huang,Shiping Ma,Zhenzhong Wang,Zheng Ma,Wei Xiao
The aim of this study was to investigate the direct inhibitory effects of Re Du Ning Injection (RDN) and its active compounds on the major cytochrome P450 enzyme (CYP) isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomes by ‘a cocktail method’. The activity of each CYP isform was represented as the formation rate of the specific metabolite from relevant substrate. Then a sensitive and specific ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed and validated to simultaneously analyze the seven metabolites. RDN (0.035–2.26 mg/mL) showed a strong inhibitiory effect on CYP2C8, followed by CYP2C9, CYP2B6, CYP2C19, CYP1A2 and CYP3A4. The IC 50 value for each enzyme was 0.19, 0.66, 0.72, 1.27, 1.66 and 2.13 mg/mL, respectively. RDN competitively inhibited the activities of CYP1A2 ( K i = 1.22 mg/mL), CYP2B6 ( K i = 0.65 mg/mL) and CYP3A4 ( K i = 0.88 mg/mL); it also exhibited mixed inhibition of CYP2C8, CYP2C9 and CYP2C19 with a K i value of 0.26, 0.64 and 0.82 mg/mL, respectively. However, the activity of CYP2D6 was not significantly inhibited even by 2.26 mg/mL RDN. Moreover, the data of nine active compounds on the CYPs showed that cryptochlorogenin acid, sochlorogenic acid B and sochlorogenic acid C were the major contributors to the inhibitory effect of RDN on CYP2C8, while the inhibitory effect of RDN on CYP2C9 might be caused by sochlorogenic acid A and sochlorogenic acid C. Moreover, neochlorogenic acid might be the major contributor to the inhibitory effect on CYP2B6. All of the findings suggested that drug–drug interactions may occur and great caution should be taken when RDN is combined with drugs metabolized by these CYPs.
研究领域:
药理学
·
临床医学
·
生物化学
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PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2018
·
IF 2.776
Min Xu,Huaqiao Tang,XueRong Zhou,Helin Chen,Qi Dong,Yuanli Zhang,Gang Ye,Fei Shi,Cheng Lv,Bo Jing,Changliang He,Ling Zhao,Yinglun Li
Copper nanoparticles (Cu NPs) have widespread application because of their special physicochemical characteristics, however we need to more clearly study the toxicity mechanism of Cu NPs to ensure its safe use in pharmaceutical and animal feed. Thus, the aim of this study was to evaluate the effects and mechanisms of sub-chronic exposure to Cu NPs on renal CYP450 s of rats. In this study, we investigated the effects of Cu NPs on renal oxidative stress, cytokines and histopathology of rats. We found that Cu NPs (200 mg/kg) significantly disordered the function and structure of the kidney and caused a dose-dependent increase in oxidative stress and cytokines, which significantly decreased the levels of mRNA, protein, and activity of CYP450 s. Micro-coppers (Cu MPs) and Cu ions have similar effects, but their effects on CYP450 s were weaker than Cu NPs. The expression of nuclear receptors were inhibited and the expression of Akt, STAT3/5, CREB, p70S6K, NF-κB, P38 and ERK1/2 were activated when the inhibition effects of CYP450 s activity were observed in renal of rats. Therefore, we believe that Cu NPs can activate the STAT, NF-κB and MAPK signaling pathways to down-regulate the expression and activity of CYP450 s by inducing oxidative stress and inflammatory response in rat kidney.
研究领域:
毒理学
·
药理学
·
分子生物学
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PubMed
高影响因子
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