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Received for publication March 23, 2005.
Revised May 6, 2005.
Accepted for publication May 25, 2005.
Multidrug resistance-associated protein 2 (Mrp2, Abcc2), an organic anion transporter present in the apical membrane of hepatocytes, renal epithelial cells and enterocytes, is postulated to undergo posttranscriptional regulation. We hypothesized that Mrp2 protein undergoes altered rates of protein synthesis or degradation consistent with different Mrp2 protein expression. We analyzed Mrp2 synthesis, expression and degradation in control female, 19 and 20-day pregnant and pregnenolone-16
-carbonitrile (PCN)-treated rats using in vivo metabolic labeling studies with 35S-cysteine/methionine or 14C-NaHCO3, polysomal distribution analyses and ribonuclease protection assays (RPA). Mrp2 protein significantly increased in rats treated with PCN for 2 days but significantly decreased in 19-day pregnant rats relative to controls; no significant differences were observed in Mrp2 mRNA expression among these groups. The measured half-lives of 14C-labelled Mrp2 in control, pregnant, and PCN-treated rats were 27, 36 and 22 hrs, respectively, and were not significantly different. The rate of incorporation of 35S into Mrp2 was highest in PCN-treated rats. Polysomal distribution analysis of Mrp2 mRNA was consistent with increased Mrp2 protein synthesis following PCN-treatment. The major transcription initiation site for rat liver determined by RPA was -98 nt, with other start sites observed at -213, -163, -132 and -71 nt; utilization of transcription sites did not differ among the groups. Differences in the degradation of Mrp2 protein cannot explain the posttranscriptional regulation of Mrp2 in control, pregnant and PCN-treated rats. Rather, the observed difference in protein synthesis suggests an intrinsic role for the translational regulation of rat Mrp2 protein.
Key words:
Organic anion, Liver transporters, Regulation - post-transcriptional, Glutathione
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