Caenorhabditis elegans as a model for nematode metabolism of the anthelmintic drugs ivermectin and albendazole

QH301 Biology;RM Therapeutics. Pharmacology

Laing, Steven ; Gilleard, John S.

University:University of Glasgow

Department:School of Veterinary Medicine

关键词: Caenorhabditis elegans, helminths, parasites, nematode, anthelmintic, anthelmintic resistance, metabolism, cytochrome P450,UDP-glucuronosyl transferase, CYP, UGT;   

Others  :  http://theses.gla.ac.uk/1781/1/2010laingphd.pdf

来源: University of Glasgow

【 摘 要 】

Resistance to anthelmintics used to treat parasitic nematodes of veterinary importance represents a serious welfare and economic problem for the livestock production industry. Research into the mechanisms by which parasites develop resistance is necessary to prolong the life of the available drugs and to minimise development of resistance to new classes. Metabolism of anthelmintic compounds by parasites is a possible mechanism of resistance that has received little research, despite there being precedence in the case of insecticide resistance. Due to the more advanced molecular tools available and comparative ease of manipulation; we have used the model nematode Caenorhabditis elegans to investigate the metabolism of two important anthelmintic drugs, ivermectin and albendazole. Whole genome microarrays and RT-QPCR were used to identify clusters of genes, which are significantly up-regulated upon exposure of C. elegans to anthelmintic. The transcriptomic response to albendazole is characterised by genes potentially involved in xenobiotic metabolism. These include members of the cytochrome P450 family and the UDP-glucuronosyl/ glucosyl transferase family. In contrast, the response to ivermectin appears to represent a fasting response caused by the phenotype of drug exposed nematodes. Recombinant worms carrying GFP reporter constructs of several genes of interest demonstrated their expression in the intestine, which is thought to be the main site of xenobiotic detoxification in nematodes. HPLC-MS techniques have definitively shown that C. elegans is able to metabolise albendazole to two glucose conjugates. These metabolites are compatible with the transcriptomic response to the drug and are similar to albendazole metabolites produced by the parasitic nematode Haemonchus contortus. No ivermectin metabolites were identified in the current study.The data presented confirms the ability of the nematode C. elegans to respond to and metabolise anthelmintic compounds. In addition, the study validates the use of C. elegans as a model organism for parasitic nematodes and provides a platform upon which to investigate nematode metabolism further.