Читать книгу Transporters and Drug-Metabolizing Enzymes in Drug Toxicity - Albert P. Li - Страница 52

APAP undergoes direct glucuronidation and sulfation, and the reactive metabolite NAPQI subjected to GSH conjugation. The various conjugates are excreted via transporter‐mediated efflux into the bile duct. Recently, using membrane vesicles, APAP–GSH was found to be substrates of MRP1, MRP2, and MRP [33]. Hepatobiliary efflux transporters MRP1 and MRP4 mRNA levels were elevated in livers from patients after toxic APAP ingestion [34]. This upregulation of transporter expression by APAP is also observed in rodent models of APAP hepatotoxicity [34–36]. Treatment of animals with clodronate liposomes to deplete Kupffer cells abolished Mrp4 upregulation by APAP as well as increasing its hepatotoxicity, suggesting that transporter upregulation is protective, and that the upregulation may be a result of Kupffer cell activation [37].