TY - JOUR
T1 - Liver Zonation Index of Drug Transporter and Metabolizing Enzyme Protein Expressions in Mouse Liver Acinuss
AU - Tachikawa, Masanori
AU - Sumiyoshiya, Yuna
AU - Saigusa, Daisuke
AU - Sasaki, Kazunari
AU - Watanabe, Michitoshi
AU - Uchida, Yasuo
AU - Terasaki, Tetsuya
N1 - Funding Information:
This study was supported in part by the Takeda Science Foundation, Mochida Memorial Foundation, and Grants-in-Aid from the Japanese Society for the Promotion of Science for Scientific Research [Grants 24249011 and 16K08364]. We thank J. Aoki for valuable discussions on LMD analysis. We also thank A. Niitomi and N. Handa for secretarial assistance.
Funding Information:
This study was supported in part by the Takeda Science Foundation, Mochida Memorial Foundation, and Grants-in-Aid from the Japanese Society for the Promotion of Science for Scientific Research [Grants 24249011 and 16K08364]. https://doi.org/10.1124/dmd.117.079244. s This article has supplemental material available at dmd.aspetjournals.org.
Publisher Copyright:
© 2018 by The American Society for Pharmacology and Experimental Therapeutics
PY - 2018/5
Y1 - 2018/5
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 periportal (PP) and pericentral (PC) vein 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-1012) 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 vein region. The protein levels of Oatp1a1, Oatp1b2, organic cation transporter 1 (Oct1), and cytochrome P450 (P450) 2e1 were greater in the PC vein regions, whereas the level of organic anion transporter 2 (Oat2) was greater in the PP vein regions. Mouse Oatp1a1 mediated SR-101 transport. On the other hand, there were no statistically significant differences in expression of Ent1, Na+-taurocholate cotransporting polypeptide, several canalicular transporters, P450 enzymes, and UDP-glucuronosyltransferases between the PP and PC vein 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.
AB - 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 periportal (PP) and pericentral (PC) vein 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-1012) 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 vein region. The protein levels of Oatp1a1, Oatp1b2, organic cation transporter 1 (Oct1), and cytochrome P450 (P450) 2e1 were greater in the PC vein regions, whereas the level of organic anion transporter 2 (Oat2) was greater in the PP vein regions. Mouse Oatp1a1 mediated SR-101 transport. On the other hand, there were no statistically significant differences in expression of Ent1, Na+-taurocholate cotransporting polypeptide, several canalicular transporters, P450 enzymes, and UDP-glucuronosyltransferases between the PP and PC vein 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.
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U2 - 10.1124/dmd.117.079244
DO - 10.1124/dmd.117.079244
M3 - Article
C2 - 29506983
AN - SCOPUS:85045842719
VL - 46
SP - 610
EP - 618
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 5
ER -