The modulation of transcriptional expression and inhibition of multidrug resistance associated protein 4 (MRP4) by analgesics and their primary metabolites
| Autor: | Carolina Inés Ghanem, José E. Manautou, Renato J. Scialis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
ATP
adenosine triphosphate Diclofenac OH-DCF 4′-hydroxy diclofenac Health Toxicology and Mutagenesis Metabolite APAP acetaminophen purl.org/becyt/ford/3.5 [https] ABCC4 Oxidative phosphorylation Pharmacology Toxicology medicine.disease_cause Applied Microbiology and Biotechnology Article chemistry.chemical_compound APAP-GLU acetaminophen glucuronide APAP-SUL acetaminophen sulfate Downregulation and upregulation ANALGESIC Fmo flavin containing monooxygenase lcsh:RA1190-1270 ALT alanine aminotransferase PGE2 prostaglandin E2 medicine DCF-AG diclofenac acyl glucuronide IS internal standard Acetaminophen Inhibition lcsh:Toxicology. Poisons Liver injury APAP-NAC acetaminophen N-acetylcysteine biology MRP4 DCF diclofenac digestive oral and skin physiology MRP multidrug resistance-associated protein Glutathione medicine.disease chemistry AMP adenosine monophosphate APAP-CYS acetaminophen cysteine biology.protein purl.org/becyt/ford/3 [https] LTC4 leukotriene C4 ACETAMINOPHEN Oxidative stress medicine.drug |
| Zdroj: | Current Research in Toxicology, Vol 1, Iss, Pp 34-41 (2020) CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET Current Research in Toxicology |
| Popis: | During the course of a toxic challenge, changes in gene expression can manifest such as induction of metabolizing enzymes as a compensatory detoxification response. We currently report that a single 400 mg/kg acetaminophen (APAP) dose to C57BL/6J mice led to an increase in multidrug resistance-associated (Mrp) 4 (Abcc4) mRNA 12 h after administration. Alanine aminotransferase, as a marker of liver injury, was also elevated indicating hepatotoxicity had occurred. Therefore, induction of Mrp4 mRNA was likely attributable to APAP-induced liver injury. Mrp4 has been shown to be upregulated during oxidative stress, and it is well-established that APAP overdose causes oxidative stress due to depletion of glutathione. Given the importance of Mrp4 upregulation as an adaptive response during cholestatic and oxidative liver injury, we next investigated the extent by which human MRP4 can be inhibited by the analgesics, APAP, diclofenac (DCF), and their metabolites. Using an in vitro assay with inside out human MRP4 vesicles, we determined that APAP-cysteine inhibited MRP4-mediated transport of leukotriene C4 with an apparent IC50 of 125 μM. APAP-glutathione also attenuated MRP4 activity though it achieved only 28% inhibition at 300 μM. Diclofenac acyl glucuronide (DCF-AG) inhibited MRP4 transport by 34% at 300 μM. The MRP4 in vitro inhibition occurs at APAP-cysteine and DCF-AG concentrations seen in vivo after toxic doses of APAP or DCF in mice, hence the findings are important given the role that Mrp4 serves as a compensatory response during oxidative stress following toxic challenge. Graphical abstract Unlabelled Image Highlights • Following 400 mg/kg APAP in mice, mean ALT 12 hours post-dose was 1,140 U/L • A statistically significant increase in Mrp4 mRNA was observed 12 hours post-dose • APAP-CYS inhibited human MRP4 transport of LTC4 with an IC50 = 125 μM (Ki = 122 μM) • APAP-GSH decreased MRP4 transport by 29% inhibition at 300 μM • APAP, APAP-GLU, APAP-NAC, and APAP-SUL did not exhibit significant MRP4 inhibition |
| Databáze: | OpenAIRE |
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