Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland, UK.
Parasitol Res. 2010 May;106(6):1351-63. doi: 10.1007/s00436-010-1806-1. Epub 2010 Mar 25.
A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 microM), then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM); MTZ+NADPH+TCBZ (15 microg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 microg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than triclabedazole-resistant isolate. However, co-incubation with MTZ+TCBZ, but more particularly MTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own, with severe swelling of the basal infolds and mucopolysaccharide masses in the syncytium, accompanied by a reduction in numbers of secretory bodies. The synthesis and production of secretory bodies in the tegumental cells was severely affected as well. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes, and this process may play a role in the development of drug resistance.
一项研究旨在探讨三氯苯达唑（TCBZ）对肝片吸虫的作用是否因药物代谢抑制而改变。使用甲巯咪唑（MTZ）抑制黄素单加氧酶系统（FMO），以观察是否可以使 TCBZ 抗性分离株对 TCBZ 作用更敏感。这些实验使用了 Oberon TCBZ 抗性和 Cullompton TCBZ 敏感分离株。通过在甲巯咪唑（100 μM）中预孵育 2 小时来抑制 FMO 系统，然后在含有 MTZ 的 NCTC 培养基中进一步孵育 22 小时；MTZ+烟酰胺腺嘌呤二核苷酸磷酸（NADPH）（1 nM）；MTZ+NADPH+TCBZ（15 μg/ml）；或 MTZ+NADPH+三氯苯达唑亚砜（TCBZ.SO）（15 μg/ml）。使用透射电子显微镜评估药物处理和代谢抑制后对吸虫超微结构的影响。单独使用 TCBZ 或 TCBZ.SO 处理后，TCBZ 敏感分离株比三氯苯达唑抗性分离株受到更大的破坏。然而，与 MTZ+TCBZ 共孵育，特别是 MTZ+TCBZ.SO，导致 TCBZ 抗性分离株的变化比每种药物单独使用更为严重，基底内褶和合胞体中的粘多糖团块严重肿胀，伴随着分泌体数量减少。表皮细胞中分泌体的合成和产生也受到严重影响。对于 TCBZ 敏感的 Cullompton 分离株，药物作用的增强有限。这些结果支持 TCBZ 抗性吸虫中药物代谢改变的概念，并且该过程可能在耐药性的发展中起作用。
