Similarities and differences in the biotransformation and transcriptomic responses of Caenorhabditis elegans and Haemonchus contortus to five different benzimidazole drugs.
Animals
Anthelmintics
/ pharmacology
Benzimidazoles
/ pharmacology
Biological Assay
Biotransformation
/ drug effects
Caenorhabditis elegans
/ drug effects
Chromatography, High Pressure Liquid
Chromatography, Liquid
Flavonoids
/ pharmacology
Glucuronosyltransferase
/ antagonists & inhibitors
Haemonchus
/ drug effects
RNA, Helminth
/ chemistry
Tandem Mass Spectrometry
Transcriptome
/ drug effects
Benzimidazoles
Caenorhabditis elegans
Haemonchus contortus
LC-MS/MS
Transcriptomic
Xenobiotic metabolism
Journal
International journal for parasitology. Drugs and drug resistance
ISSN: 2211-3207
Titre abrégé: Int J Parasitol Drugs Drug Resist
Pays: Netherlands
ID NLM: 101576715
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
18
05
2019
revised:
05
09
2019
accepted:
08
09
2019
pubmed:
23
9
2019
medline:
15
5
2020
entrez:
23
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31542693
pii: S2211-3207(19)30077-6
doi: 10.1016/j.ijpddr.2019.09.001
pmc: PMC6796749
pii:
doi:
Substances chimiques
Anthelmintics
0
Benzimidazoles
0
Flavonoids
0
RNA, Helminth
0
chrysin
3CN01F5ZJ5
UGT1A1 enzyme
EC 2.4.1.-
Glucuronosyltransferase
EC 2.4.1.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13-29Subventions
Organisme : CIHR
ID : 230927
Pays : Canada
Informations de copyright
Copyright © 2019. Published by Elsevier Ltd.
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