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 metabolism we describe increases the susceptibility of C. elegans to TBZ in wild-type and in resistant genetic backgrounds.
Highlights
In humans, oxidation reactions by cytochrome P450 (CYP) enzymes play an important role in the metabolism of a vast number of endogenous and exogenous compounds
We have recently shown that members of the CYP family are induced by thiabendazole [TBZ; 2-(4-thiazolyl)-1H-benzimidazole] in C. elegans and that the most inducible CYP with the highest expression and for the longest duration is regulated by nhr-176 [9]
We have shown previously that nhr-176 is required for induction of cyp-35d1 by TBZ [9]
Summary
Oxidation reactions by cytochrome P450 (CYP) enzymes play an important role in the metabolism of a vast number of endogenous and exogenous compounds. This superfamily is responsible for the bio-transformation of approximately 90 % of commonly used pharmaceuticals [1]. The human genome contains 57 predicted CYPs, divided among 18 families and 44 subfamilies [2]. Three of these families (CYP1, CYP2 and CYP3) are responsible for drug and steroid metabolism, with CYP3A and especially CYP3A4 being the most important in humans [3]
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