PUBLICATION
Regulation of hepatic abcb4 and cyp3a65 gene expression and multidrug/multixenobiotic resistance (MDR/MXR) functional activity in the model teleost, Danio rerio (zebrafish)
- Authors
- Jackson, J.S., Kennedy, C.J.
- ID
- ZDB-PUB-170619-2
- Date
- 2017
- Source
- Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 200: 34-41 (Journal)
- Registered Authors
- Keywords
- Biotransformation, CYP450, Efflux, Fish, Ketoconazole, Multi-xenobiotic resistance, P-glycoprotein, PCN, Pxr
- MeSH Terms
-
- Liver/drug effects
- Liver/metabolism*
- Pregnenolone Carbonitrile/metabolism
- Aryl Hydrocarbon Hydroxylases/genetics
- Aryl Hydrocarbon Hydroxylases/metabolism*
- Gene Expression Regulation/physiology*
- Drug Resistance/genetics*
- Ketoconazole/pharmacology
- Cytochrome P-450 CYP3A Inhibitors/pharmacology
- Animals
- Oxidoreductases, N-Demethylating/genetics
- Oxidoreductases, N-Demethylating/metabolism*
- Rhodamines/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism*
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 28624525 Full text @ Comp. Biochem. Physiol. C Toxicol. Pharmacol.
Citation
Jackson, J.S., Kennedy, C.J. (2017) Regulation of hepatic abcb4 and cyp3a65 gene expression and multidrug/multixenobiotic resistance (MDR/MXR) functional activity in the model teleost, Danio rerio (zebrafish). Comparative biochemistry and physiology. Toxicology & pharmacology : CBP. 200:34-41.
Abstract
Multidrug/multixenobiotic resistance (MDR/MXR) confers resistance to a diverse range of potentially toxic pharmaceuticals and environmental contaminants through a cellular response that involves the coordinated induction and activity of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) and the Phase I metabolizing enzyme cytochrome P450 3A (CYP3A). In mammals, ligand-mediated pregnane X receptor (PXR) transcriptional activity regulates the induction of P-gp and CYP3A; however, this mechanism has not been well-characterized in fish. Zebrafish (Danio rerio) treated with the Pxr agonist pregnenolone 16?-carbonitrile (PCN) showed decreased P-gp (zebrafish Abcb4) and CYP3A (zebrafish Cyp3a65) mRNA levels after 48 h exposure; however, treatment with PCN also resulted in increased hepatic MDR/MXR functional activity (i.e. increased Rhodamine 123 efflux) in vivo. Consistent with mammalian-like MDR/MXR regulated by PXR, the PCN-mediated modulation of hepatic Abcb4 and Cyp3a65 mRNA levels and MDR/MXR functional activity was attenuated by co-treatment with PCN and the mammalian PXR antagonist, ketoconazole (KTC). These results provide evidence that zebrafish Pxr may play a role in MDR/MXR through transcriptional regulation of abcb4 and cyp3a65 gene expression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping