Decreased expression of P-glycoprotein during differentiation in the human intestinal cell line Caco-2.
The expression profile of the multidrug resistance (MDR) 1 gene product P-glycoprotein (Pgp) was examined during culture using Caco-2 cells as an in vitro model. Levels of MDR1 and cyclooxygenase 2 mRNA expression in Caco-2 cells were the highest on day 3 and decreased with days in culture, but the level of cyclooxygenase 1 was stable throughout the culture period. The stability of MDR1 mRNA was 7-fold higher on day 3 than on day 9, and the run-on assay suggested the transcription rate of the MDR1 gene on day 3 tended to be higher than on day 9. In addition, the expression of Pgp was comparable with that of MDR1 mRNA, but was inversely correlated with villin expression. The Pgp-mediated tacrolimus transport was the highest on day 1 and the lowest on day 11. These results suggested that the changeable mRNA stability rather than transcription rate of MDR1 contributed to its up-regulation during cell proliferation and down-regulation after post-confluent differentiation in Caco-2 cells. Therefore, the temporal induction and subsequent down-regulation of the enterocyte Pgp could affect bioavailability of several drugs during the regeneration of the intestinal wall.
Goto
Maki
M
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Masuda
Satohiro
S
Saito
Hideyuki
H
Inui
Ken-ichi
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D001692:Biological Transport; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D007422:Intestines / Q000473:pathology; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger