Abstract
The involvement of the canalicular multidrug resistance protein 2 (Mrp2) in the hepatobiliary excretion of acetaminophen (APAP)-glutathione (GSH) conjugate and its derivatives was investigated using transport-deficient (TR- rats. Although no differences in the biliary concentration of APAP itself were detected between normal Wistar and TR- rats, significant differences in the biliary disposition of several conjugated metabolites of APAP were detected. APAP-GSH was virtually absent in bile from TR- rats. Also, biliary concentrations of APAP-mercapturate (NAC; N-acetylated l-cysteine) and APAP-GLU were significantly reduced in TR- rats. No differences in the biliary concentration of APAP-cysteinylglycine/cysteine (CG/CYS) were detected between normal and mutant rats. The cumulative amounts of APAP-CG/CYS and APAP-NAC excreted in urine of mutant rats were decreased, whereas APAP-GLU was markedly increased. Analysis of liver samples revealed that APAP-GSH and APAP-NAC accumulate in mutant rat livers. Our results support the direct involvement of Mrp2 in the hepatobiliary excretion of several conjugated metabolites of APAP, including APAP-GSH and APAP-NAC, and provide relevant information on processes that may be involved with both their hepatic basolateral transport and renal elimination.
Footnotes
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↵ 1 Abbreviations used are: APAP, acetaminophen; GSH, glutathione; APAP-GSH, acetaminophen-glutathione; APAP-CG/CYS, acetaminophen-cysteinylglycine/cysteine; APAP-NAC, acetaminophen-mercapturate (N-acetylated l-cysteine); APAP-GLU, acetaminophen-glucuronide; APAP-SUL, acetaminophen-sulfate; ICG, indocyanine green; Mrp1, 2, and 3, multidrug resistance protein 1, 2, and 3; GSSG, glutathione disulfide; TR-rat, transport-deficient rat; EHBR, Eisai hyperbilirubinemic rat; HPLC, high-performance liquid chromatography.
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This work was supported in part by National Institutes of Health Grant ES10093 and a Boehringer Ingelheim Pharmaceutical, Inc. Predoctoral Fellowship in Toxicology to C.C. This work was presented at the 40th Annual Meeting of the Society of Toxicology, 2001 Mar 16–29; San Francisco, CA.
- Received June 21, 2002.
- Accepted March 12, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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