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Similarities and differences in the biotransformation and transcriptomic responses of Caenorhabditis elegans and Haemonchus contortus to five different benzimidazole drugs.
International Journal for Parasitology: Drugs and Drug Resistance ( IF 4.1 ) Pub Date : 2019-09-09 , DOI: 10.1016/j.ijpddr.2019.09.001
S J Stasiuk 1 , G MacNevin 1 , M L Workentine 1 , D Gray 2 , E Redman 1 , D Bartley 3 , A Morrison 3 , N Sharma 1 , D Colwell 2 , D K Ro 1 , J S Gilleard 1
Affiliation  

We have undertaken a detailed analysis of the biotransformation of five of the most therapeutically important benzimidazole anthelmintics - albendazole (ABZ), mebendazole (MBZ), thiabendazole (TBZ), oxfendazole (OxBZ) and fenbendazole (FBZ) - in Caenorhabditis elegans and the ruminant parasite Haemonchus contortus. Drug metabolites were detected by LC-MS/MS analysis in supernatants of C. elegans cultures with a hexose conjugate, most likely glucose, dominating for all five drugs. This work adds to a growing body of evidence that glucose conjugation is a major pathway of xenobiotic metabolism in nematodes and may be a target for enhancement of anthelmintic potency. Consistent with this, we found that biotransformation of albendazole by C. elegans reduced drug potency. Glucose metabolite production by C. elegans was reduced in the presence of the pharmacological inhibitor chrysin suggesting that UDP-glucuronosyl/glucosyl transferase (UGT) enzymes may catalyze benzimidazole glucosidation. Similar glucoside metabolites were detected following ex vivo culture of adult Haemonchus contortus. As a step towards identifying nematode enzymes potentially responsible for benzimidazole biotransformation, we characterised the transcriptomic response to each of the benzimidazole drugs using the C. elegans resistant strain CB3474 ben-1(e1880)III. In the case of albendazole, mebendazole, thiabendazole, and oxfendazole the shared transcriptomic response was dominated by the up-regulation of classical xenobiotic response genes including a shared group of UGT enzymes (ugt-14/25/33/34/37/41/8/9). In the case of fenbendazole, a much greater number of genes were up-regulated, as well as developmental and brood size effects suggesting the presence of secondary drug targets in addition to BEN-1. The transcriptional xenobiotic response of a multiply resistant H. contortus strain UGA/2004 was essentially undetectable in the adult stage but present in the L3 infective stage, albeit more muted than C. elegans. This suggests that xenobiotic responses may be less efficient in stages of parasitic nematodes that reside in the host compared with the free-living stages.

中文翻译:

Caenorhabditis elegans 和 Haemonchus contortus 对五种不同苯并咪唑药物的生物转化和转录组反应的异同。

我们对五种最重要的苯并咪唑驱虫药——阿苯达唑 (ABZ)、甲苯咪唑 (MBZ)、噻苯达唑 (TBZ)、奥芬达唑 (OxBZ) 和芬苯达唑 (FBZ)——在秀丽隐杆线虫和反刍动物中的生物转化进行了详细分析寄生虫 扭曲血矛线虫。通过 LC-MS/MS 分析在线虫培养物的上清液中检测到药物代谢物,其中己糖偶联物(最有可能是葡萄糖)在所有五种药物中占主导地位。这项工作增加了越来越多的证据表明葡萄糖结合是线虫中外源性代谢的主要途径,并且可能是增强驱虫效力的目标。与此一致,我们发现秀丽隐杆线虫对阿苯达唑的生物转化降低了药物效力。葡萄糖代谢物的生产 C. 在存在药理学抑制剂白杨素的情况下,线虫减少,这表明 UDP-葡萄糖醛酸基/葡萄糖基转移酶 (UGT) 酶可能催化苯并咪唑糖苷化。在成年捻转血矛线虫体外培养后检测到类似的葡萄糖苷代谢物。作为识别可能导致苯并咪唑生物转化的线虫酶的一步,我们使用秀丽隐杆线虫抗性菌株 CB3474 ben-1(e1880)III 对每种苯并咪唑药物的转录组反应进行了表征。在阿苯达唑、甲苯咪唑、噻苯达唑和奥芬达唑的情况下,共同的转录组反应主要由经典外源性反应基因的上调控制,包括一组共同的 UGT 酶 (ugt-14/25/33/34/37/41/ 8/9)。在芬苯达唑的情况下,更多的基因被上调,以及发育和育雏大小的影响,表明除了 BEN-1 之外还存在次要药物靶点。多重抗性 H. contortus 菌株 UGA/2004 的转录外源性反应在成年阶段基本上无法检测到,但存在于 L3 感染阶段,尽管比 C. elegans 更温和。这表明与自由生活阶段相比,寄生线虫在寄生线虫阶段的外源性反应可能效率较低。尽管比秀丽隐杆线虫更安静。这表明与自由生活阶段相比,寄生线虫在寄生线虫阶段的外源性反应可能效率较低。尽管比秀丽隐杆线虫更安静。这表明与自由生活阶段相比,寄生线虫在寄生线虫阶段的外源性反应可能效率较低。
更新日期:2019-11-01
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