Altered expression of sulfotransferases, glucuronosyltransferases and mrp transporters in FVB/mrp1-/- mice.

1. Genetically altered mice increasingly are being used in toxicology and pharmaceutical development. As such, knowledge of the compensatory activity of enzymes is critical when interpreting the results of studies using these animals. 2. The present study examined alterations in hepatic phase I and II enzyme activity, and alterations in phase III (transporter) RNA expression, between FVB mice and mice lacking the multidrug resistance-associated protein 1 (mrp1) gene (FVB/mrp1-/- mice). It was hypothesized that other transporters and phase I and II enzymes would be increased in the FVB/mrp1-/- mice, presumably as a compensatory mechanism. 3. No differences was found in hepatic cytochrome P450 activity between FVB and FVB/mrp1-/- mice, nor were there differences in the amount of total hepatic glutathione or in glutathione S-transferase enzyme activity. 4. However, sulfotransferase activity towards 2-naphthol was significantly increased by 2.6-fold in the FVB/mrp1-/- mice, whereas glucuronosyltransferase activity towards both 4-nitrophenol and testosterone was significantly reduced 1.5-fold. In addition, mrp2 RNA expression was significantly increased by 3.4-fold and mrp5 expression was significantly increased by 1.6-fold in the FVB/mrp1-/- mice. 5. Mice lacking mrp1 have significantly increased hepatic transcription of at least two other ATP-binding cassette transporters, as well as increased 2-naphthol sulfotransferase activity, presumably to compensate for the lack of mrp1.