Abstract
Chemicals that activate nuclear factor-E2-related factor-2 (Nrf2) often increase multidrug resistance-associated protein expression in liver. Hepatocyte-specific deletion of Kelch-like ECH-associated protein 1 (
Keap1)
activates Nrf2. Use of hepatocyte-specific
Keap1
deletion represents a non-pharmacological method to determine whether constitutive Nrf2 activation upregulates liver transporter expression
in vivo
. The mRNA, protein expression and localization of several biotransformation and transporters was determined in livers of wild-type and hepatocyte-specific
Keap1
-null mice. Sulfotransferase 2a1/2, NADP(H):quinone oxidoreductase 1, Cytochrome P450 2b10, 3a11, and glutamate-cysteine ligase catalytic subunit expression was increased in livers of
Keap1
-null mice. Oatp1a1 expression was nearly abolished, as compared to that detected in livers of wild-type mice. By contrast, Mrp 1-5 mRNA and protein levels were increased in
Keap1
-null mouse livers, with Mrp4 expression being more than 15-fold higher than wild-types. In summary, Nrf2 has a significant role in affecting expression of Oatp and Mrp expression.