Results
Title

NHR-176 regulates cyp-35d1 to control hydroxylation-dependent metabolism of thiabendazole in Caenorhabditis elegans.

Authors

Jones, Laura M.; Flemming, Anthony J.; Urwin, Peter E.

Abstract

Knowledge of how drugs are metabolized and excreted is an essential component of understanding their fate within and among target and non-target organisms. Thiabendazole (TBZ) was the first benzimidazole (BZ) to be commercially available and remains one of the most important anthelmintic drugs for medical and veterinary use. We have characterized how Caenorhabditis elegans metabolizes and excretes TBZ.We have shown that TBZ directly binds to the nuclear hormone receptor (NHR)-176 and that this receptor is required for the induction by TBZ of the cytochrome P450 (CYP) encoded by cyp-35d1. Further, RNAi inhibition of cyp-35d1 in animals exposed to TBZ causes a reduction in the quantity of a hydroxylated TBZ metabolite and its glucose conjugate that is detected in C. elegans tissue by HPLC. This final metabolite is unique to nematodes and we also identify two P-glycoproteins (PGPs) necessary for its excretion. Finally, we have shown that inhibiting the metabolismwe describe increases the susceptibility of C. elegans to TBZ in wild-type and in resistant genetic backgrounds.

Subjects

THIABENDAZOLE; ANTHELMINTICS; CAENORHABDITIS elegans; NUCLEAR receptors (Biochemistry); RNA interference; HYDROXYLATION; DRUG metabolism; THERAPEUTICS

Publication

Biochemical Journal, 2015, Vol 466, Issue 1, p37

ISSN

0264-6021

Publication type

Academic Journal

DOI

10.1042/BJ20141296