JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Kun Ren,Xuanmeng Zhang,Ruijie Wang,Shumeng Ren,Huiming Hua,Dongmei Wang,Yingni Pan,Xiaoqiu Liu
Ethnopharmacological relevance Euodiae Fructus (EF), the dried, unripe, scented fruit of Tetradium ruticarpum (A. Juss, T.G.Hartley), is a traditional food and herb with mild toxicity. In Asia, it is processed with licorice (EFP), which has been used for centuries to alleviate pain and suppress cough. Pharmacological studies have reported that this herb could cause liver injury by activating the P450 3A enzyme, thus carrying the risk of clinical application. Processing with licorice is an effective method to reduce EF toxicity. It is urgent to explore the toxic components of EF and the attenuation mechanism of licorice. Aim of the study This study aimed to indicate the specific pathway of EF-induced damage and identify the mechanism of action of licorice in reducing P450 activation and resulting in reduced liver damage. Materials and methods Male C57BL-6 mice were used to investigate the toxicity of EF to the liver and determine the attenuation effect on P450 from licorice ingestion. Glutathione (GSH) was used to capture the metabolic activation intermediates of EF. The key component reducing the EF toxicity of licorice was investigated by comparing the differences in chemical components and inhibition on the EF metabolism of licorice from different habitats. Results The intermediate product of evodiamine (EVO) in EF was found to be activated by the P450 enzyme during metabolism, causing liver injury and inflammation. Isoliquiritigenin and liquiritigenin in licorice produced by intestinal bacterial metabolism and glycyrrhizin inhibited the metabolic activation of EF. Glycosides in licorice are metabolized into aglycones by intestinal bacteria , inhibiting the metabolic activation of EF and alleviating hepatotoxicity. Conclusions By combining with GSH, the electrophilic intermediates produced by the P450 enzyme's metabolic activation of the indole ring of EVO might cause hepatotoxicity. Glycyrrhizin from licorice and the liquiritigenin and isoliquiritigenin generated by intestinal bacterial metabolism play an attenuated function by inhibiting the P450 enzyme and preventing the metabolic activation of EF.
研究领域:
药理学
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毒理学
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中医药学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2019
·
IF 4.18
Shuai Ji,Dan-dan He,Zhen-yu Su,Yan Du,Yu-jie Wang,Shi-kai Gao,Meng-zhe Guo,Dao-quan Tang
Background Herbal compatibility of compound formulas can enhance therapeutic effects or reduce side effects of the monarch drugs , but majority of compatibility mechanisms are still unknown. Sangju-Yin, a well-known Chinese compound formula, is currently used to treat common cold in clinical. Purpose In this study, we proposed a strategy to explore the compatibility mechanism of Sangju-Yin by investigating P450 enzymes-based metabolic interactions between monarch drugs and the other constituent herbs. Methods Under the guidance of traditional Chinese medicine theory, the constituent herbs of Sangju-Yin were divided into four groups, including monarch drugs, monarch drugs with addition of minister drugs, monarch drugs with addition of minister and adjuvant drugs, as well as the whole recipe, namely monarch drugs with addition of minister, adjuvant and conductant drugs. Their effects on rats in vivo P450 (CYP1A2, CYP2A3, CYP2C6, CYP2C11 and CYP3A1) activities after oral administration were evaluated using probe drug assay based on LC-MS/MS. Moreover, effects of the four groups of herbs on mRNA expression of P450 enzymes after oral administration, as well as in vitro P450 activities after co-incubation, were investigated to explore the underlying mechanisms. Results Comparing with monarch drugs, addition of different constituent herbs significantly enhanced CYP1A2 and CYP2C6 activities, and inhibited CYP2A3 and CYP3A1 activities, indicating their possible influences on plasma concentrations of active constituents in the monarch drugs. Mechanism study suggested that these herbs affected P450 activities by transcriptional regulation and/or direct interaction with the enzymes. Conclusion This study clarified the compatibility mechanism of Sangju-Yin from the aspect of P450 enzymes-based metabolic interactions, which would benefit better understanding of the therapeutic basis of Sangju-Yin.
研究领域:
中药学
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药物代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2018
·Vol. 19
·期 7
·2140
·
IF 3.687
Huaqiao Tang,Min Xu,Fei Shi,Gang Ye,Cheng Lv,Jie Luo,Ling Zhao,Yinglun Li
Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals.Keywords:nano-copper;oral exposure;liver toxicity;CYP450 enzymes;mechanism
研究领域:
毒理学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Natural Product Communications
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2019
·
IF 0.554
Keling Cheng,Xuan Zeng,Hao Wu,Weiwei Su,Weiyang Fan,Yang Bai,Hongliang Yao,Peibo Li
Naringin (NRG) is a common dietary flavonoid in citrus fruits and has been documented to possess multiple pharmacological activities, including anti-oxidant, anti-inflammatory, and neuroprotective effects. Naringin is frequently consumed in combination with common clinical drugs. To date, the effects of NRG on cytochrome P450 enzymes have not been fully investigated yet. In this study, the activities of hepatic CYP1A2, CYP2D2, CYP2C9, CYP2C19, and CYP2E1 in rats after the continuous oral administration of NRG (50 and 500 mg/kg) were evaluated using cocktail probe-drug method. The concentrations of 5 probe drugs (phenacetin, dextromethorphan, diclofenac sodium, omeprazole, and chlorzoxazone) in rat plasma were simultaneously determined with a validated HPLC-MS/MS (high performance liquid chromatography-tandem mass spectrometry) method and then used to calculate corresponding pharmacokinetic parameters. Compared with the control group, the AUC(0-t), AUC(0-∞), t 1/2, and C max of each probe drug in treatment groups showed no significant differences. Meanwhile, fluorescence quantitative polymerase chain reaction (FQ-PCR) analysis revealed that NRG did not significantly affect the mRNA expressions of genes CYP1a2, CYP2d2, CYP2c6, CYP2c11, and CYP2e1 in rat liver. Based on these results, it could be concluded that NRG showed no significant effects on the activities and mRNA expressions of tested CYP450 in rats.
研究领域:
药理学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2025
·
IF 4
Fang-Rui Guo,Shu-Chao Wang,Yan Liu,Shuai Wang,Jing-Mei Huang,Hao Sun,Lin-Feng He,Yuan Xie,Song-Tao Qiao,Feng-Xia Yang,Chris Bass,Cong-Fen Gao,Shun-Fan Wu
The development of insecticide resistance in insect populations is a major challenge to sustainable agriculture and food security worldwide. Methoxyfenozide, an insect growth regulator that acts as an agonist of 20-hydroxyecdysone (20E), has severely declined in its efficacy against the rice stem borer ( Chilo suppressalis ), a notorious pest of rice crops in East and Southeast Asia. To date, however, the genes involved in methoxyfenozide resistance in target pests remain unclear. We conducted a long-term (seven years from 2017 to 2023) and large geographical scale (8 provinces and 45 cities in China) resistance monitoring program for methoxyfenozide in C. suppressalis . Resistance was seen to arise rapidly in this species, with >100-fold resistance being detected in nearly all the field populations after 2018 . Piperonyl butoxide (PBO), an inhibitor of cytochrome P450 enzymes (P450s), significantly increased the sensitivity of resistant strains of C. suppressalis to methoxyfenozide, implicating P450s in resistance. Six P450 genes: CYP321F3, CYP6CV5, CYP9A68 , CYP6AB45, CYP324A12 and CYP6SN2 were identified as highly expressed in resistant C. suppressalis by transcriptome profiling. Of these, ectopic expression of CYP321F3 in Drosophila melanogaster resulted in a 7.0-fold increase in resistance to methoxyfenozide demonstrating its causal role in resistance. Collectively, these findings provide insight into the mechanisms mediating resistance to insect growth regulators and will inform the development of future pest and resistance management strategies.
研究领域:
昆虫学
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分子生物学
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农业科学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2025
·
IF 2.9
Siyu Liu,Guode Zhao,Yingyun Xu,Yang Wang,Zifang Ding,Weiwei Li,Ying Peng,Jiang Zheng
Osthole (OST), a coumarin derivative, is one of the major components of Cnidium monnieri (L.) Cussion. OST was reported to induce apoptosis in hepatocytes. Elevated serum ALT and AST were documented in Sprague-Dawley rats after administration of OST. In the present study, OST was found to be metabolized to a phenol metabolite which was further metabolically oxidized to the corresponding quinone methide intermediate. A glutathione conjugate derived from the reactive metabolite was detected in vitro and in vivo . The structures of the metabolites were verified by chemical analysis. CYP3A4 and CYP1A2 were the major enzymes to catalyze the oxidation reactions. Pre-treatment with 1-aminobenzotriazole or ketoconazole decreased the susceptibility of primary hepatocytes to the cytotoxicity of OST. The findings provided solid evidence that the metabolic activation of OST correlated with the cytotoxicity of OST.
研究领域:
药理学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2019
·
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2018
·Vol. 46
·期 4
·442-450
·
IF 3.64
Huimin Zhao,Siyuan Li,Zixin Yang,Ying Peng,Xiaohui Chen,Jiang Zheng
Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of nonsmall cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of cytochrome P450(CYPs) 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent. CYPs 3A4 and 3A5 mainly contributed to the bioactivation of ELT. Microsomal incubation study showed that the ketene intermediate covalently modified the enzyme protein at lysine residues and destroyed the structure of heme. The vinyl and ethyl analogs of ELT showed minor enzyme inhibitory effect (less than 20%), whereas ELT inactivated more than 60% of the enzyme. The present study provided a novel bioactivation pathway of ELT and facilitated the understanding of the mechanisms of ELT-induced mechanism-based enzyme inactivation and liver injury.
研究领域:
药理学
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毒理学
·
药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Synthetic Biology
·
2025
·
IF 3.9
Baodong Hu,Jingwen Zhou,Jianghua Li,Jian Chen,Guocheng Du,Fang Zhong,Yucheng Zhao,Xinrui Zhao
Marmesin, a plant dihydrofuranocoumarin, is an important intermediate in the synthesis of linear furanocoumarins and exhibits a variety of pharmacological activities. However, due to the lack of efficient prenyltransferases, the incompatibility of redox partners for P450 enzymes, and the insufficient supply of precursor (DMAPP), the microbial synthesis of marmesin remained at an extremely low level. Here, we report the efficient biosynthesis of marmesin in Escherichia coli by screening the robust 6-prenyltransferase PpPT1 and marmesin synthase PpDCΔ2–29 from Peucedanum praeruptorum. Next, the activities of PpPT1 and PpDCΔ2–29 were enhanced using fusion protein tags and redox partner engineering, respectively. In addition, the synthesis of marmesin was further improved by strengthening the methylerythritol phosphate (MEP) pathway to increase the availability of DMAPP and by optimizing the modular pathway in the engineered strain. Finally, the titer of marmesin reached 203.69 mg L–1 in the fed-batch fermentation with a molar conversion rate of umbelliferone of 81.4%, which is the highest titer for marmesin production using engineered microorganisms. The applied strategy and marmesin-producing strain constructed in this study lay the foundation for the green production of valuable complex furanocoumarins.
研究领域:
生物化学
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合成生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2022
·Vol. 23
·期 13
·1054-1066
·
IF 3.408
Chai Yuan-Yuan,Xu Yun-Xia,Xia Zi-Yin,Li An-Qin,Huang Xin,Zhang Lu-Yong,Jiang Zhen-Zhou
Background: The use of herbal medicines has tremendously increased over the past few decades. Case reports and controlled clinical investigations of herbal-drug interactions have been reported. Since Cytochrome P450 (CYP) enzymes play an important role in drug interactions. The evaluation
of the influence of herbal medicines on the activities of CYPs is beneficial to promote scientific and rational clinical use of herbal medicines. Objective: Herein, we aimed to develop and validate a method to simultaneously quantify seven CYP cocktail probe drugs consisting of phenacetin
(PNC), bupropion (BPP), losartan potassium (LK), omeprazole (OMP), dextromethorphan (DM), chlorzoxazone (CZZ) and midazolam (MDZ) and their respective metabolites in a single acquisition run and use this method to evaluate the influence of Zhuanggu Guanjie Pill (ZGGJP) on seven CYPs.
Methods: A cost-effective and simple UHPLC-(±)ESI-MS/MS method for simultaneous determination of seven probe drugs and metabolites in rat plasma was developed and validated. Male and female rats were randomly divided into three groups and treated with 1.2 g/kg/d ZGGJP, 5 g/kg/d ZGGJP
and 0.5% CMC-Na for 14 consecutive days. After 24 h of the last administration, all rats were administrated orally with probe drugs. The influence of ZGGJP on the CYPs was carried out by comparing the metabolic ratio (Cmax, AUC0-t) of metabolites/probe
drugs in rats. Results: The calibration curves were linear, with correlation coefficient > 0.99 for seven probe drugs and their corresponding metabolites. Intra- and inter-day precisions were not greater than 15% RSD and the accuracies were within ± 15% of nominal concentrations.
The ZGGJP showed significant inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats. Conclusion: ZGGJP had inductive effects on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats.
研究领域:
药理学
·
临床药学
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中药学
✓ 已验证
DOI
PubMed
高影响因子
ENZYME AND MICROBIAL TECHNOLOGY
·
2019
·
IF 3.553
Kui Wu,Ying Zhang,Qingdi Sun,Yuxin Chai,Qian He,Xiantai Zhou,Xiaohui He,Hongbing Ji
A novel hybrid material with flower-mimicking morphology was fabricated with a facile coprecipitation method, and cytochrome P450 enzyme and cobalt phosphate were employed as organic and inorganic components, respectively. The hybrid nano-flowers showed excellent catalytic performance in the oxidative coupling of benzylamine, including the high conversion (99.9%) and selectivity (97.9%) in mild reaction conditions, as well as the satisfactory stability in the recycling experiments. Compared to free enzyme, the as-obtained materials exhibited enhanced activity. Such results indicate that the hybrid materials are potentially good candidates in the industrial enzyme catalysis.
研究领域:
生物化学
·
材料科学
·
酶工程
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）