JOURNAL OF APPLIED ENTOMOLOGY
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2022
·Vol. 146
·期 7
·823-837
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IF 2.183
Xuanyu He,Zhaodong Hao,Hui Li,Tian Xu,Ruixu Chen,Xiaohong Xia,Shouyin Li,Dejun Hao
Understanding the mechanism of insect resistance to toxic effects of phytochemicals can provide an insight into plant–herbivore interactions. Monochamus alternatus Hope, a main vector of pine wood nematode ( Bursaphelenchus xylophilus ), prefers to infest masson pine ( Pinus massoniana Lamb) and causes huge economic and environmental losses. α-Pinene is the primary component of resin produced by masson pine and plays a crucial role in defending against herbivorous insects, but its defensive effects on M . alternatus larvae are barely known. Here, we explored the physiological metabolism in M . alternatus larvae that were fumigated with (+)-α-pinene, (-)-α-pinene, β-pinene, (R)-(+)-limonene, myrcene and (-)-α-phellandrene. (+)-α-Pinene showed the highest fumigant toxicity to M . alternatus larvae among these monoterpenes, and the fourth instar larvae possessed the highest resistance to this compound at the larval stage. Comparative transcriptome analysis detected 423 up-regulated and 311 down-regulated genes in the larvae fumigated with (+)-α-pinene, which were mainly related to detoxification, energy and protein metabolism. Among the differentially expressed genes encoding for detoxification enzymes, 14 P450s, 13 UGTs, 1GSTs and 3ABCs were dramatically up-regulated in the larvae fumigated with (+)-α-pinene. Silencing of P450s via RNA interference led to an increased mortality in the larval fumigated with (+)-α-pinene. Piperonyl butoxide exposure significantly increased the mortality and inhibited the expressions of P450s, UGTs and ABCs in the larvae fumigated with (+)-α-pinene. These results suggested an important role of P450s in the resistance of M . alternatus larvae to (+)-α-pinene fumigation, which may facilitate the understanding of terpenoid detoxification in M . alternatus larvae.
研究领域:
昆虫学
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分子生物学
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植物-昆虫互作
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DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2020
·
IF 6.205
Shenzhi Zhou,Wei Li,Min Tian,Na Zhang,Xiaojing Yang,Weiwei Li,Ying Peng,Jiang Zheng
Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis. Idiosyncratic drug reactions, due to clinical application of pirfenidone, have been documented, even along with death cases resulting from acute liver failure. The present study aimed at the investigation of metabolic activation of pirfenidone possibly participating in the reported adverse reactions. Pirfenidone-derived glutathione/N-acetylcysteine (GSH/NAC) conjugates were detected in microsomal/primary hepatocyte incubations after exposure to pirfenidone. The GSH/NAC conjugates were also observed in bile and urine of rats given pirfenidone, respectively. The observation of the conjugates suggests the formation of a quinone methide intermediate derived from pirfenidone. The intermediate was possibly generated through two pathways. First, pirfenidone was directly metabolized to the quinone methide intermediate via dehydrogenation; second, pirfenidone was oxidized to 5-hydroxymethyl pirfenidone, followed by sulfation to a benzyl alcohol-sulfate derivative. The findings facilitate the understanding of the mechanisms of pirfenidone-induced idiosyncratic toxicity and assist medicinal chemists to minimize toxicities in the development of new pharmaceutical agents.
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高影响因子
BIORESOURCE TECHNOLOGY
·
2023
·
IF 11.4
Guojuan Yi,Hanlu Zou,Tao Long,Tolbert Osire,Lin Wang,Xiaoyun Wei,Mengfei Long,Zhiming Rao,Guojian Liao
Hydroxylated steroids are value-added products with diverse biological activities mediated by cytochrome P450 enzymes, however, few has been thoroughly characterized in fungi. This study introduces a rapid identification strategy for filamentous fungi P450 enzymes through transcriptome and bioinformatics analysis. Five novel enzymes (CYP68J5, CYP68L10, CYP68J3, CYP68N1 and CYP68N3) were identified and characterized in Saccharomyces cerevisiae or Aspergillus oryzae . Molecular docking and dynamics simulations were employed to elucidate hydroxylation preferences of CYP68J5 (11α, 7α bihydroxylase) and CYP68N1 (11α hydroxylase). Additionally, redox partners (cytochrome P450 reductase and cytochrome b5) and ABC transporter were co-expressed with CYP68N1 to enhance 11α-OH-androstenedione (11α-OH-4AD) production. The engineered cell factory, co-expressing CPR1 and CYP68N1, achieved a significant increase of 11α-OH-4AD production, reaching 0.845 g·L -1 , which increased by 14 times compared to the original strain. This study provides a comprehensive approach for identifying and implementing novel cytochrome P450 enzymes, paving the way for sustainable production of steroidal products.
研究领域:
分子生物学
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生物化学
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生物技术
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真菌遗传学
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PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2022
·Vol. 30
·期 15
·42587-42595
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IF 5.19
Yu Haikuo,Yang Xianmei,Dai Jinghua,Li Yuning,Veeran Sethuraman,Lin Jintian,Shu Benshui
The fall armyworm, Spodoptera frugiperda, has become a worldwide pest and threatens world food production. A previous study indicated that azadirachtin, the most effective botanical insecticide for S. frugiperda , inhibits larval growth of the insect. The effect of azadirachtin on the tissues of the larvae, however, remains to be determined. In this study, the effects of azadirachtin on the structure of fat bodies were analyzed. Comparative transcriptomic analysis was conducted between controls and samples treated with 0.1 μg/g azadirachtin for 7 days to explore potential relevant mechanisms. The expression of 5356 genes was significantly affected after azadirachtin treatment, with 3020 up-regulated and 2336 down-regulated. Among them, 137 encode detoxification enzymes, including 53 P450s , 20 GSTs , 27 CarEs , 16 UGTs , and 12 ABC transporters . Our results indicated that azadirachtin could destroy fat body structure and change the mRNA levels of detoxification-related genes. The up-regulated genes encoding detoxification enzymes might be related to detoxifying azadirachtin. Our results elucidate a preliminary mechanism of azadirachtin detoxification in the fat bodies of S. frugiperda larvae.
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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PubMed
高影响因子
JOURNAL OF ELECTROANALYTICAL CHEMISTRY
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2016
·
IF 2.822
Li Shangguan,Yuewu Zhao,Li Mi,Ling Jiang,Songqin Liu
In the present work, gold nanoparticles coated chitosan/reduced graphene oxide (Au-CS-RG) was prepared for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 1A1 (CYP1A1) immobilization, investigation of the direct electrochemistry and electrochemically-driven drug metabolism. The immobilized CYP2D6 and CYP1A1 displayed respectively a pair of redox peaks with a formal potential of − 492 ± 4 and − 504 ± 6 mV. The response showed a surface-controlled electrode process with an average electron transfer rate constant of 5.19 ± 0.3 s − 1 for CYP2D6 and 3.24 ± 0.4 s − 1 for CYP1A1 determined in the scan rate of 100 mV/s. When the Au-CS-RG was treated with polyacrylic acid (PAA), the resulting nanocomposites (PAA-Au-CS-RG) changed the surface charge of Au-CS-RG from positive to negative and increased the size of the coated gold nanoparticles from ~ 15 to ~ 25 nm. This led to negative-shift of the formal potential to − 513 ± 6 mV for CYP2D6 and − 509 ± 5 mV for CYP1A1, while the electron transfer rate constant decreased to 4.10 ± 0.3 s − 1 for CYP2D6 and 2.78 ± 0.2 s − 1 for CYP1A1, respectively. The immobilized CYP2D6 and CYP1A1 in both cases showed excellent electrochemically-driven drug metabolism. The LC-MS analysis demonstrated the bioconversion from tramadol or benzo[ a ]pyrene to o -demethyl-tramadol or 7.8-diol benzo[ a ]pyrene by the electrochemically-driven way, respectively. The metabolic inhibition of the quinidine and alpha-naphthoflavone to the enzymatic activity of CYP2D6 and CYP1A1 were also evaluated.
研究领域:
生物化学
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材料科学
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药理学
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DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Shuaibing Liu,Shiyu Zhao,XueXia Zhang,Eric Chun Yong Chan,Ziteng Wang,Hang Li,Xin Tian
Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent K m values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 μM, while V max values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent K m value for metabolism of infigratinib to CQM157 by HLM is 0.049 μM, while the V max value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.
研究领域:
药理学
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临床医学
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生物化学
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PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY
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2016
·
IF 1.651
Lulu Dai,Mingyuan Ma,Guanqun Gao,Hui Chen
Bark beetles oxidize the defensive allelochemicals of their host trees both to detoxify them and convert them into components of their pheromone systems which were catalyzed by cytochrome P450 enzymes (CYPs) and occur in different tissues of the insect. We study P450 genes in the Chinese white pine beetle ( Dendroctonus armandi ), and some bio-information analysis was done for the full-length deduced amino acid sequences. The tissue specificity of these P450 genes was determined in three tissues (antenna, gut and reproductive organs). Differential expression of the P450 genes was observed between sexes, and within these significant differences exposed to stimuli (α-pinene (1:1 racemic mix), (S)-(−)-α-pinene, (S)-(−)-β-pinene, (+)-3-carene, (±)-limonene and turpentine oil) at 24 h. Increased expression of P450 genes suggested that they play a role in the detoxification of monoterpenes released by the host trees. The different transcript accumulation patterns of these bark beetle P450 genes provided insight into ecological interactions of D . armandi with its host pine.
研究领域:
昆虫学
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分子生物学
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生态学
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生物信息学
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DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2019
·
IF 2.87
Kai Tian,Jiang Zhu,Mei Li,Xinghui Qiu
Capsaicin (8-methyl- N -vanillyl-6-nonenamide) is the most abundant capsaicinoids found in hot peppers ( Capsicum annum and Capsicum frutescens ). It has been well documented that capsaicin plays an important role in the defense against the attack of herbivores or pathogens on Capsicum plants. A few insect herbivores such as Helicoverpa armigera and Helicoverpa assulta have been recorded to be capable of feeding on hot pepper fruits, suggesting that these insects evolve mechanisms against the toxicity of capsaicin. Although cytochrome P450-meidated detoxification is considered to be an important mechanism by which cotton bollworms cope with capsaicin, experimental evidence is lacking. In this study, we compared the capacity of four H. armigera P450s (CYP6B6, CYP9A12, CYP9A14 and CYP9A17) in capsaicin metabolism, and the capsaicin metabolites were screened and tentatively identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). HPLC analyses showed that depletion rates of capsaicin were 21.9 ± 0.1, 11.9 ± 1.5, 16.3 ± 1.4 and 14.8 ± 0.2 min −1 for CYP6B6, CYP9A12, CYP9A14 and CYP9A17 respectively. The transformation of capsaicin was inhibited by the P450 inhibitor piperonyl butoxide . A total of seven products were detected, and hydroxylation (aromatic and aliphatic) and dehydrogenation were found to be two main pathways in capsaicin metabolism. In addition, capsaicin metabolism was enzyme selective: M1 (ω-hydroxylated N-macrocyclic metabolite) and M3 (ω-hydroxylated metabolite) were uniquely detected in the CYP6B6 catalytic reaction, while M4 (ω-n hydroxylated capsaicin), M5 (diene of capsaicin) and M6 (doubly oxidized metabolite of dehydrogenated capsaicin) were only detectable in CYP9A metabolisms. A capsaicin dimer (5, 5′-dicapsaicin) was found to be the major metabolite of CYP9A reactions, but the minor product produced by CYP6B6. An overall more similar behavior in capsaicin metabolism was observed among CYP9As than between CYP6B6 and CYP9As. Our data demonstrate that CYP6B6 and CYP9As have a potent capability to transform capsaicin, and individual P450 produce unique metabolite profile. These findings help us to understand the molecular basis of capsaicin adaptation in H. armigera .
研究领域:
昆虫学
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植物化学
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分子生物学
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PubMed
高影响因子
Insects
·
2021
·Vol. 12
·期 7
·651
·
IF 2.769
Xiaorong Xing,Mengwen Yan,Huilin Pang,Fu’an Wu,Jun Wang,Sheng Sheng
Simple SummaryP450s are involved in the detoxification process in insects; however, less attention has been paid for their roles in parasitoid wasps. Here, we identified 28 P450s from the previous constructed transcriptome dataset ofMeteorus pulchricornisand validated their expression patterns under insecticides exposure. Furthermore, we silencedCYP369B3in adult wasps and demonstrated that the knocking downCYP369B3significantly increased of the mortality of adult wasps when they were exposed to each chemical insecticide, phoxim, cypermethrin, and chlorfenapyr, respectively. The present study provides a theoretical base for functional research on P450 genes in parasitoid wasps.AbstractWith the widespread application of insecticides, parasitoid wasps may also be under risk when exposed to insecticides directly at their free-living stages. The endoparasitoid waspMeteorus pulchricornisis the predominant natural enemy of many lepidopteran pests, such asSpodoptera lituraandHelicoverpa armigera. The cytochrome P450 monooxygenases constitute a ubiquitous and complex superfamily of hydrophobic, haem-containing enzymes. P450s are involved in the detoxification of many xenobiotics. However, their exact roles in the tolerance mechanism in parasitoids toward insecticides has received less attention. Here, 28 P450 genes inM. pulchricorniswere identified from a previously constructed transcriptome dataset. These P450 genes belonged to CYP2, -3, and -4, and mitochondrial clans. Subsequently, eight candidateMpulCYPswere selected from four CYP clans to validate their expression patterns under phoxim, cypermethrin, and chlorfenapyr exposure by qRT-PCR. The results showed that all three insecticides had significant effects on the expression ofMpulCYPs. To further study the function of P450s,CYP369B3was silenced, and its expression levels ofCYP369B3were significantly decreased. Survival analysis indicated that after dsRNA injection, the mortality rate of wasps was significantly increased whenM. pulchricornisfemales were exposed to insecticides compared to control groups. Our findings provide a theoretical base for elucidating the mechanism of insecticide tolerance and promote functional research on P450 genes in parasitoid wasps.Keywords:Meteorus pulchricornis;cytochrome P450s;detoxification;insecticide tolerance
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
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2026
·
IF 4.8
Tengfei Xiong,Jiang Zhu,Mei Li,Xinghui Qiu
The use of various insecticides has resulted in insecticide resistance in many populations of pest insects. CYP6D1 and CYP6G4 are two cytochrome P450s that have been recruited to confer insecticide resistance in the house fly populations, yet the biochemical basis for their roles in insecticide metabolism is not fully understood. Here, we used recombinant enzymes to explore the capacity of the two field-evolved resistance-conferring P450s from house flies in the metabolism of 16 commonly used insecticides. The chemical structure of the detectable metabolite was identified by liquid chromatography coupled with mass spectrometry. Moreover, we analyzed the structural features associated with substrate selectivity between the two P450s through AlphaFold-based modeling and substrate docking. We found that both CYP6D1 and CYP6G4 were able to metabolize multiple classes of structurally diverse insecticides via substrate-dependent catalytic reactions including dealkylation, desulfurization and hydroxylation. Molecular modeling predicted that CYP6D1 possesses a larger solvent-accessible V-shaped pocket that accommodates bulky substrates such as esfenvalerate, whereas CYP6G4 has a more compact architecture that favors smaller substrates like acetamiprid and methomyl. We propose that the intrinsically broad substrate spectra of CYP6D1 and CYP6G4, together with their regulatory evolvability and negligible fitness costs, collectively predispose these two P450s to recurrent selection among the 146 P450 genes in the housefly genome in field populations. These findings advance our understanding of the evolutionary principles governing P450-mediated insecticide resistance, and provide a biochemical framework for designing evidence-based pest management strategies.
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高影响因子
JOURNAL OF TOXICOLOGICAL SCIENCES
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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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PubMed
高影响因子
Toxics
·
2026
·Vol. 14
·期 8
·691
·
IF 4.9
Zhao Zhou,Hongbin Gao,Shunda Zhu,Lvlue Cai,Yijing Chen,Keqi Hu,Yungang Liu
As a commonly present organophosphorus flame retardant and persistent organic pollutant, 2-ethylhexyl diphenyl phosphate (EHDPP) has been observed to be genotoxic in cultured human hepatoma (HepG2) cells which depends on CYP activities. Yet, its impacts on hepatic Cyp expression, hepatotoxicity and genotoxicity in intact mammalians remain unidentified. In this study, adult male C57BL/6J mice received EHDPP by gastric gavage at doses of 50, 100, and 150 mg/kg (b.w.)/d for 7 d, then the hepatic expression of several Cyp proteins, aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) was analyzed by Western blotting; hepatoxicity was determined by serum ALT/AST activities and hepatic histological examination, while genotoxicity by comet assay, phosphorylated histone (γ-H2AX) protein, micronucleus test, and Pig-a assay. A micronucleus test in mouse hepatoma (Hepa1-6) cells in vitro was employed to observe the modulating effect of PCB 126 (100 nM)/BAY-218 (700 nM) (Ahr-Cyp1a1 activator/inhibitor). The results indicated that EHDPP induced hepatic Cyp1a1, 2e1, AhR, Cyp1a2, Cyp3a4 and PXR proteins and histologic liver damage at 50 mg/kg/d and/or higher doses, while at the highest dose (150 mg/kg/d) with hepatic DNA damage and micronucleus formation in bone marrow polychromatic erythrocytes. The result of Pig-a assay (at 14 and 28 d) was negative. In Hepa1-6 cells EHDPP induced micronucleus marginally; however, this effect was enhanced by PCB 126, while abolished by BAY-218. This study suggests that EHDPP may enhance protein expression of hepatic Cyp1a1, Cyp2e1, AhR and PXR and induce liver damage and DNA/chromosome damage in mice; Cyp1a1 might be a major activating enzyme.
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高影响因子
危险品化学品经营许可证（带存储）