TY - JOUR T1 - Liver zonation index of drug transporter and metabolizing enzyme protein expressions in mouse liver acinus JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.079244 SP - dmd.117.079244 AU - Masanori Tachikawa AU - Yuna Sumiyoshiya AU - Daisuke Saigusa AU - Kazunari Sasaki AU - Michitoshi Watanabe AU - Yasuo Uchida AU - Tetsuya Terasaki Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/03/05/dmd.117.079244.abstract N2 - The purpose of the present study was to clarify the molecular basis of zonated drug distributions in mouse liver based on the protein expression levels of transporters and metabolizing enzymes in peri-portal vein (PP) and peri-central vein (PC) regions of mouse hepatic lobules. The distributions of sulforhodamine 101 (SR-101), a substrate of organic anion transporting polypeptides (Oatps), and ribavirin, a substrate of equilibrative nucleoside transporter 1 (Ent1), were elucidated in frozen liver sections of mice to which each compound had been intravenously administered. Regions strongly positive for SR-101 [SR-101(+)] and regions weakly positive or negative for SR-101 [SR-101(-)] were separated by laser microdissection. The zonated distribution of protein expression was quantified in terms of the liver zonation index. Quantitative targeted absolute proteomics revealed the selective expression of glutamine synthetase in the SR-101(+) region, indicating predominant distribution of SR-101 in hepatocytes of the PC region. The protein levels of Oatp1a1, Oatp1b2, organic cation transporter 1 (Oct1), and cytochrome P450 (Cyp) 2e1 were greater in PC regions, whereas the level of organic anion transporter (Oat) 2 was greater in PP regions. Mouse Oatp1a1 mediated SR-101 transport. On the other hand, there were no statistically significant differences in expression of Ent1, Ntcp, several canalicular transporters, Cyp enzymes, and UDP-glucuronosyltransferases between the PP and PC regions. This is consistent with the almost uniform distribution of ribavirin in the liver. In conclusion, sinusoidal membrane transporters such as Oatp1a1, Oatp1b2, Oct1, and Oat2 appear to be determinants of the zonated distribution of drugs in the liver. ER -