Stephanie van Hoppe

130 Chapter 6 Table 1 lists the various Oatp1a and Oatp1b knockout strains, and OATP1A/1B humanized strains that have been described so far. Oatp1a1 and Oatp1a4 knockout strains were described by Ose et al. (2010) and Gong et al. (2011). These mouse strains, originally made in 129/Ola ES cells by Deltagen, were backcrossed 10 times to a C57BL/6 background, and subsequent characterization of these lines was mainly done in this genetic background. A few independent Oatb1b2 knockout strains were generated. Lu et al. (2008) described the generation and initial characterization of an Oatp1b2 knockout strain generated in 129S1 ES cells, which was backcrossed for 7 generations to a C57BL/6 background. Independently, Zaher et al. (2008) generated Oatp1b2 knockout mice using DBA1/lacJ ES cells, which were further kept and characterized in a DBA1/ lacJ genetic background. Combined Oatp1a/1b knockout mice, covering all the mouse Oatp1a and Oatp1b genes, were generated in 129/Ola ES cells. Initial characterization of Oatp1a/1b(-/-) mice was done in a mixed (~50%) 129/Ola and FVB genetic background (van de Steeg et al., 2010), but this strain was subsequently backcrossed for at least 7 generations to an FVB background, in which further characterization took place (van de Steeg et al., 2012). These FVB background Oatp1a/1b(-/-) mice were then used to generate three different humanized mouse strains with predominant expression of human OATP1A2, OATP1B1, or OATP1B3 cDNA, respectively, in the liver parenchyme cells, again all in FVB background (van de Steeg et al., 2012; van de Steeg et al., 2013). Moreover, a combined humanized OATP1B1/OATP1B3 strain was created by crossing the separate transgenic strains (Salphati et al., 2014). Table 1 - Oatp1a/b mouse models. Mouse models Genetic background Primary references Oatp1a1 knockout C57Bl/6N (Gong et al., 2011) Oatp1a4 knockout C57Bl/6N (Gong et al., 2011; Ose et al., 2010) Oatp1b2 knockout (variant 1) C57BL/6 (Lu et al., 2008) Oatp1b2 knockout (variant 2) DBA1/lacJ (Zaher et al., 2008) Oatp1a/1b knockout FVB (van de Steeg et al., 2010) Humanized hepatic OATP1A2 transgenic FVB (van de Steeg et al., 2013) Humanized hepatic OATP1B1 transgenic FVB (van de Steeg et al., 2009) Humanized hepatic OATP1B3 transgenic FVB (van de Steeg et al., 2013) Humanized hepatic OATP1B1 and OATP1B3 transgenic FVB (Salphati et al., 2014) 1 . 3 . C ave a t s i n u s i ng OATP1A / 1B gene t i c a l l y mod i f i ed mou s e mode l s It should be noted that the genetic background strain may at times be important for the extent to which certain phenotypes are detectable in knockout and transgenic mice.