Full Text:   <1785>

Summary:  <1545>

CLC number: R965.3

On-line Access: 2020-01-03

Received: 2019-07-12

Revision Accepted: 2019-09-04

Crosschecked: 2019-12-17

Cited: 0

Clicked: 2592

Citations:  Bibtex RefMan EndNote GB/T7714


Gen Chen


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.1 P.77-86


Toxicity and metabolism of 3-bromopyruvate in Caenorhabditis elegans

Author(s):  Qiao-ling Gu, Yan Zhang, Xi-mei Fu, Zhao-lian Lu, Yao Yu, Gen Chen, Rong Ma, Wei Kou, Yong-mei Lan

Affiliation(s):  The Institute of Minority Physique and Health, Medical College of Northwest University for Nationalities, Lanzhou 730030, China; more

Corresponding email(s):   chengen1999@163.com

Key Words:  3-Bromopyruvate, Caenorhabditis elegans, Hexokinase, Cytochrome P450

Qiao-ling Gu, Yan Zhang, Xi-mei Fu, Zhao-lian Lu, Yao Yu, Gen Chen, Rong Ma, Wei Kou, Yong-mei Lan. Toxicity and metabolism of 3-bromopyruvate in Caenorhabditis elegans[J]. Journal of Zhejiang University Science B, 2020, 21(1): 77-86.

@article{title="Toxicity and metabolism of 3-bromopyruvate in Caenorhabditis elegans",
author="Qiao-ling Gu, Yan Zhang, Xi-mei Fu, Zhao-lian Lu, Yao Yu, Gen Chen, Rong Ma, Wei Kou, Yong-mei Lan",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Toxicity and metabolism of 3-bromopyruvate in Caenorhabditis elegans
%A Qiao-ling Gu
%A Yan Zhang
%A Xi-mei Fu
%A Zhao-lian Lu
%A Yao Yu
%A Gen Chen
%A Rong Ma
%A Wei Kou
%A Yong-mei Lan
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 1
%P 77-86
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1900370

T1 - Toxicity and metabolism of 3-bromopyruvate in Caenorhabditis elegans
A1 - Qiao-ling Gu
A1 - Yan Zhang
A1 - Xi-mei Fu
A1 - Zhao-lian Lu
A1 - Yao Yu
A1 - Gen Chen
A1 - Rong Ma
A1 - Wei Kou
A1 - Yong-mei Lan
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 1
SP - 77
EP - 86
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1900370

In this study, we aimed to evaluate the toxic effects, changes in life span, and expression of various metabolism-related genes in Caenorhabditis elegans, using RNA interference (RNAi) and mutant strains, after 3-Bromopyruvate (3-BrPA) treatment. C. elegans was treated with various concentrations of 3-BrPA on nematode growth medium (NGM) plates, and their survival was monitored every 24 h. The expression of genes related to metabolism was measured by the real-time fluorescent quantitative polymerase chain reaction (qPCR). Nematode survival in the presence of 3-BrPA was also studied after silencing three hexokinase (HK) genes. The average life span of C. elegans cultured on NGM with 3-BrPA was shortened to 5.7 d compared with 7.7 d in the control group. hxk-1, hxk-2, and hxk-3 were overexpressed after the treatment with 3-BrPA. After successfully interfering hxk-1, hxk-2, and hxk-3, the 50% lethal concentration (LC50) of all mutant nematodes decreased with 3-BrPA treatment for 24 h compared with that of the control. All the cyp35 genes tested were overexpressed, except cyp-35B3. The induction of cyp-35A1 expression was most obvious. The LC50 values of the mutant strains cyp-35A1, cyp-35A2, cyp-35A4, cyp-35B3, and cyp-35C1 were lower than that of the control. Thus, the toxicity of 3-BrPA is closely related to its effect on hexokinase metabolism in nematodes, and the cyp-35 family plays a key role in the metabolism of 3-BrPA.


目的:通过3-溴丙酮酸(3-BrPA)处理秀丽隐杆线虫(Caenorhabditis elegans),观察3-BrPA对线虫的毒性和生存周期的影响.通过秀丽隐杆线虫RNA干扰(RNAi)和突变株,分析3-BrPA对线虫糖酵解途径己糖激酶家族和药物代谢的关键酶细胞色素P450(cytochrome P450,CYP)家族的影响.
方法:用不同浓度的3-BrPA处理秀丽隐杆线虫,每24 h监测一次存活率;用实时荧光定量聚合酶链反应(qPCR)检测代谢相关基因的表达;通过RNAi沉默己糖激酶家族基因hxk-1hxk-2hxk-3;计算3-BrPA处理hxk家族RNAi株和细胞色素P450 cyp-35家族突变株后的致死中浓度(LC50).
结论:3-BrPA对线虫有明显的毒性效应(图1);与对照组比较,3-BrPA处理组的线虫平均寿命明显缩短(图2);3-BrPA处理线虫后hxk-1hxk-2hxk-3的信使RNA(mRNA)表达明显升高(P<0.05,图5);3-BrPA处理hxk RNAi株后的LC50均减小(P<0.05,表5);3-BrPA处理cyp-35突变株后的LC50也均减小(P<0.05,表6).综上所述,3-BrPA的毒性与其对秀丽隐杆线虫己糖激酶代谢的影响密切相关;CYP-35家族在线虫中对3-BrPA代谢中起着关键作用.


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Alcántar-Aguirre FC, Chagolla A, Tiessen A, et al., 2013. ATP produced by oxidative phosphorylation is channeled toward hexokinase bound to mitochondrial porin (VDAC) in beetroots (Beta vulgaris). Planta, 237(6):1571-1583.

[2]Cárdenas ML, Cornish-Bowden A, Ureta T, 1998. Evolution and regulatory role of the hexokinases. Biochim Biophys Acta, 1401(3):242-264.

[3]Chen FZ, Wang H, Lai JD, et al., 2018. 3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: in vitro and in vivo studies. Int J Cardiol, 266:236-241.

[4]Chen GH, Zhang YD, Liang JF, et al., 2018. Deregulation of hexokinase II is associated with glycolysis, autophagy, and the epithelial-mesenchymal transition in tongue squamous cell carcinoma under hypoxia. BioMed Res Int, 2018:8480762.

[5]de Meis L, Grieco MAB, Galina A, 1992. Reversal of oxidative phosphorylation in submitochondrial particles using glucose 6-phosphate and hexokinase as an ATP regenerating system. FEBS Lett, 308(2):197-201.

[6]Dewaal D, Nogueira V, Terry AR, et al., 2018. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun, 9:446.

[7]Dyląg M, Lis P, Niedźwiecka K, et al., 2013. 3-Bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans. Biochem Biophys Res Commun, 434(2):322-327.

[8]el Sayed SM, Baghdadi H, Zolaly M, et al., 2017. The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: an evidence-based view. Med Hypotheses, 100:67-77.

[9]García-Espiñeira MC, Tejeda-Benítez LP, Olivero-Verbel J, 2018. Toxic effects of bisphenol A, propyl paraben, and triclosan on Caenorhabditis elegans. Int J Environ Res Public Health, 15(4):684.

[10]Guengerich FP, 2008. Cytochrome P450 and chemical toxicology. Chem Res Toxicol, 21(1):70-83.

[11]Huang RT, Huang Q, Wu GL, et al., 2017. Evaluation of the antioxidant property and effects in Caenorhabditis elegans of Xiangxi flavor vinegar, a Hunan local traditional vinegar. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 18(4):324-333.

[12]Kim JS, Ahn KJ, Kim JA, et al., 2008. Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells: ROS-mediated cell death by 3-BrPA. J Bioenerg Biomembr, 40(6):607-618.

[13]Kim W, Yoon JH, Jeong JM, et al., 2007. Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma. Mol Cancer Ther, 6(9):2554-2562.

[14]Lai CH, Chou CY, Ch'ang LY, et al., 2000. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res, 10(5):703-713.

[15]Menzel R, Bogaert T, Achazi R, 2001. A systematic gene expression screen of Caenorhabditis elegans cytochrome P450 genes reveals CYP35 as strongly xenobiotic inducible. Arch Biochem Biophys, 395(2):158-168.

[16]Mycielska ME, Moser C, Wagner C, et al., 2012. Abstract 3211: inhibition of Hsp90 impairs expression of VDAC in plasma and mitochondrial membrane influencing cancer cell metabolism. Cancer Res, 72(S8):3211.

[17]Olsen BB, Gjedde A, Vilstrup MH, et al., 2019. Linked hexokinase and glucose-6-phosphatase activities reflect grade of ovarian malignancy. Mol Imaging Biol, 21(2):375-381.

[18]Patra KC, Hay N, 2013. Hexokinase 2 as oncotarget. Oncotarget, 4(11):1862-1863.

[19]Patra KC, Wang Q, Bhaskar PT, et al., 2013. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell, 24(2):213-228.

[20]Qiao Y, Zhao YL, Wu QL, 2014. Full toxicity assessment of Genkwa Flos and the underlying mechanism in nematode Caenorhabditis elegans. PLoS ONE, 9(3):e91825.

[21]Roh JY, Choi J, 2011. Cyp35a2 gene expression is involved in toxicity of fenitrothion in the soil nematode Caenorhabditis elegans. Chemosphere, 84(10):1356-1361.

[22]Slein MW, Cori GT, Cori CF, 1950. A comparative study of hexokinase from yeast and animal tissues. J Biol Chem, 186(2):763-780.

[23]Wilson JE, 2003. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol, 206:2049-2057.

[24]Xu D, Jin JZ, Yu H, et al., 2017. Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2. J Exp Clin Cancer Res, 36(1):44.

[25]Yadav S, Pandey SK, Kumar A, et al., 2017a. Antitumor and chemosensitizing action of 3-bromopyruvate: implication of deregulated metabolism. Chem Biol Interact, 270:73-89.

[26]Yadav S, Pandey SK, Singh VK, et al., 2017b. Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: implication in designing of novel anticancer therapeutic strategies. PLoS ONE, 12(5):e0176403.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE