TY - JOUR
T1 - Application of Quantitative Targeted Absolute Proteomics to Profile Protein Expression Changes of Hepatic Transporters and Metabolizing Enzymes During Cholic Acid-Promoted Liver Regeneration
AU - Miura, Takayuki
AU - Tachikawa, Masanori
AU - Ohtsuka, Hideo
AU - Fukase, Koji
AU - Nakayama, Shun
AU - Sakata, Naoaki
AU - Motoi, Fuyuhiko
AU - Naito, Takeshi
AU - Katayose, Yu
AU - Uchida, Yasuo
AU - Ohtsuki, Sumio
AU - Terasaki, Tetsuya
AU - Unno, Michiaki
N1 - Publisher Copyright:
© 2017 American Pharmacists Association®
PY - 2017/9
Y1 - 2017/9
N2 - Preoperative administration of cholic acid (CA) may be an option to increase the liver volume before elective liver resection surgery, so it is important to understand its effects on liver functionality for drug transport and metabolism. The purpose of this study is to clarify the absolute protein expression dynamics of transporters and metabolizing enzymes in the liver of mice fed with CA-containing diet for 5 days (CA1) and mice fed with CA-containing diet for 5 days followed by diet without CA for 7 days (CA2), in comparison with non-CA-fed control mice. The CA1 group showed the increased liver weight, cell proliferation index, and oxidative stress, but no increase in apoptosis. Quantitative targeted absolute proteomics revealed (1) decreases in basolateral bile acid transporters Na+-taurocholate cotransporting polypeptide, anion transporting polypeptide (oatp) 1a1, and oatp1b2, bile acid synthesis-related enzymes cyp7a1 and cyp8b1, and drug transporters breast cancer resistance protein, multidrug resistance-associated protein 6, ent1, and oatp2b1; and (2) increases in glutathione biosynthetic enzymes and drug-metabolizing enzyme cyp3a11. Liver concentrations of reduced and oxidized glutathione were both increased. In the CA2 group, the increased liver weight was maintained, whereas the biochemical features and protein profiles were restored to the non-CA-fed control levels. These findings suggest that CA administration alters liver functionality per body during liver regeneration and restoration.
AB - Preoperative administration of cholic acid (CA) may be an option to increase the liver volume before elective liver resection surgery, so it is important to understand its effects on liver functionality for drug transport and metabolism. The purpose of this study is to clarify the absolute protein expression dynamics of transporters and metabolizing enzymes in the liver of mice fed with CA-containing diet for 5 days (CA1) and mice fed with CA-containing diet for 5 days followed by diet without CA for 7 days (CA2), in comparison with non-CA-fed control mice. The CA1 group showed the increased liver weight, cell proliferation index, and oxidative stress, but no increase in apoptosis. Quantitative targeted absolute proteomics revealed (1) decreases in basolateral bile acid transporters Na+-taurocholate cotransporting polypeptide, anion transporting polypeptide (oatp) 1a1, and oatp1b2, bile acid synthesis-related enzymes cyp7a1 and cyp8b1, and drug transporters breast cancer resistance protein, multidrug resistance-associated protein 6, ent1, and oatp2b1; and (2) increases in glutathione biosynthetic enzymes and drug-metabolizing enzyme cyp3a11. Liver concentrations of reduced and oxidized glutathione were both increased. In the CA2 group, the increased liver weight was maintained, whereas the biochemical features and protein profiles were restored to the non-CA-fed control levels. These findings suggest that CA administration alters liver functionality per body during liver regeneration and restoration.
KW - drug-metabolizing enzymes
KW - hepatic metabolism
KW - hepatic transport
KW - metabolism
KW - organic anion-transporting polypeptide transporters
KW - pharmacokinetics
KW - transporters
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U2 - 10.1016/j.xphs.2017.02.018
DO - 10.1016/j.xphs.2017.02.018
M3 - Article
C2 - 28249806
AN - SCOPUS:85017117506
VL - 106
SP - 2499
EP - 2508
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 9
ER -