| RRC ID |
45762
|
| Author |
Jones LM, Flemming AJ, Urwin PE.
|
| Title |
NHR-176 regulates cyp-35d1 to control hydroxylation-dependent metabolism of thiabendazole in Caenorhabditis elegans.
|
| Journal |
Biochem J
|
| 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.
|
| Volume |
466(1)
|
| Pages |
37-44
|
| Published |
2015-2-15
|
| DOI |
10.1042/BJ20141296
|
| PII |
BJ20141296
|
| PMID |
25406993
|
| MeSH |
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Animals
Anthelmintics / metabolism*
Anthelmintics / pharmacology
Biotransformation
Caenorhabditis elegans / drug effects
Caenorhabditis elegans / genetics
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism*
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism*
Gene Expression Profiling
Gene Expression Regulation
Glucose / metabolism
Hydroxylation
Protein Isoforms / genetics
Protein Isoforms / metabolism
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Thiabendazole / metabolism*
Thiabendazole / pharmacology
|
| IF |
4.097
|
| Times Cited |
14
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| C.elegans |
tm0830
tm0333 |
