Daily rhythms of P-glycoprotein expression in mice.
Recent studies have shown the gene expression of several transporters to be circadian rhythmic. However, it remains to be elucidated whether the expression of P-glycoprotein, which is involved in the transport of many medications, undergoes 24 h rhythmicity. To address this issue, we investigated daily profiles of P-glycoprotein mRNA and protein levels in peripheral mouse tissues. In the liver and intestine, but not in the kidney, Abcb1a mRNA expression showed clear 24 h rhythmicity. On the other hand, Abcb1b and Abcb4, the other P-glycoprotein genes, did not exhibit significant rhythmic expression in the studied tissues. In the intestine, levels of whole P-glycoprotein also exhibited a daily rhythm, with a peak occurring in the latter half of the light phase and a trough at the onset of the light phase. Consistent with the day-night change of P-glycoprotein level, the ex vivo accumulation of digoxin, an Abcb1a P-glycoprotein substrate, into the intestinal segments at the onset of dark phase was significantly lower than it was at the onset of the light phase. Thus, Abcb1a P-glycoprotein expression, and apparently its function, are 24 h rhythmic at least in mouse intestine tissue. This circadian variation might be involved in various chronopharmacological phenomena.
Ando
Hitoshi
H
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical School, Minami-kawachi, Tochigi, Japan.
Yanagihara
Hayato
H
Sugimoto
Koh-ichi
K
Hayashi
Yohei
Y
Tsuruoka
Shuichi
S
Takamura
Toshinari
T
Kaneko
Shuichi
S
Fujimura
Akio
A
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis*; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D004077:Digoxin / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000502:physiology*; D007583:Jejunum / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D012333:RNA, Messenger; D004077:Digoxin