Stephanie van Hoppe

129 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice on overlapping substrates just based on amino acid similarity. As the tissue distribution is also not conserved between members of one subfamily (for instance, mouse Oatp1a1 and Oatp1a4 are present in the sinusoidal membrane of hepatocytes, whereas human OATP1A2 is not) it is clear that one cannot use single-gene mouse Oatp1a or Oatp1b knockout strains tomake reliable predictions on the in vivo behavior of humanOATP1A2, OATP1B1, or OATP1B3. This was an important motivation to generate a complete Oatp1a/1b knockout strain, and use it to specifically express human OATP1A2, OATP1B1, and OATP1B3 in this knockout background (van de Steeg et al., 2012; van de Steeg et al., 2013; van de Steeg et al., 2010). Figure 1 - Comparison of the human and mouse OATP1A/B/C gene clusters. The human OATP1A/ B/C gene cluster is located on chromosome 12p. OATP1C1 is followed by OATP1B3, the OATP1B- like pseudogene LST-3 (OATP1B7 according to Ensembl), OATP1B1, and OATP1A2. OATP1A2 is transcribed from the opposite strand compared to the OATP1B- and OATP1C-type genes in the cluster. The mouse Oatp1a/b/c genes are located on chromosome 6p in a similar order as the human genes, starting with Oatp1c1 followed by Oatp1b2, Oatp1a-like pseudogene A (Ensembl: Gm5724), Oatp1a4, Oatp1a1, Oatp1a-like pseudogene B (Ensembl: Gm6614), Oatp1a6, and Oatp1a5. Analogous to the human gene cluster, all Oatp1a-type genes (and pseudogenes) are oriented in the opposite transcripion direction of the Oatp1b- and Oatp1c-type genes. The relative sizes and distances of the genes are depicted roughly to scale, also between the mouse and human chromosome, but without showing exon/intron structures, and arrows indicate the direction of transcription. Pseudogenes and their putative direction of transcription are rendered hatched. Directions of centromeres and telomeres and the approximate size of the human and mouse gene clusters are indicated. Fi ure 1: Comparis n of the human and mouse OATP1A/B/ gene c ust rs. The human OATP1A/B/C gene cluster is located on chromosome 12p. OATP1C1 is followed by OATP1B3, the OATP1B-like pseudogene LST-3 (OATP1B7 according to Ensembl), OATP1B1, and OATP1A2. OATP1A2 is transcribed from the opposite strand compared to the OATP1B- and OATP1C-type genes in the cluster. The mouse Oatp1a/b/c genes are located on chromosome 6p in a similar order as the human genes, starting with Oatp1c1 followed by Oatp1b2, Oatp1a-like pseudogene A (Ensembl: Gm5724), Oatp1a4, Oatp1a1, Oatp1a-like pseudogene B (Ensembl: Gm6614), Oatp1a6, and Oatp1a5. Analogous to the human gene cluster, all Oatp1a-type genes (and pseudogenes) are oriented in the opposite transcripion direction of the Oatp1b- and Oatp1c-type genes. The relative sizes and distances of the genes are depicted roughly to scale, also between the mouse and human chromosome, but without showing exon/intron structures, and arrows indicate t e direction of transcription. Pseudogenes and their putative direction of transcripti ar rendered h tched. Direc ions of c ntr meres d telomeres and th approximat size of the human and mouse g ne clusters are indicated. B Oatp1a5 Oatp1a4 Oatp1b2 Human chromosome 12 Mouse chromosome 6 OATP1C1 OATP1B3 LST-3 OATP1B1 Telomere OATP1A2 Centromere Telomere Centromere Oatp1c1 A Oatp1a1 Oatp1a6 708 Kb 799 Kb