Acute digoxin loading reduces ABCA8A mRNA expression in the mouse liver.
Human ABCA8, a new member of the ATP binding cassette (ABC) transporter family, transports certain lipophilic drugs, such as digoxin. To investigate the roles of this transporter, we cloned a mouse homologue of ABCA8, from a mouse heart cDNA library, named ABCA8a. The deduced mouse ABCA8a protein is 66% identical with that of human ABCA8 and possesses features common to the ABC superfamily. It was found that ABCA8a was mainly expressed in the liver and heart, similar to human ABCA8. We further evaluated the effect of acute digoxin (a substrate for ABCA8) intoxication on the mRNA expression of ABCA8 using northern blotting with a 3' non-coding region as a probe to avoid cross-hybridization with other ABCA genes. Following acute digoxin infusion, the mRNA expression of ABCA8 was significantly reduced in the liver 12-24 h after injection (14.7% of vehicle treatment), but not in the heart and kidney. Real-time quantitative polymerase chain reaction analysis confirmed the reduction in ABCA8a mRNA. Similar reductions in ABCA5, ABCA7, ABCA8b and ABCA9 mRNA were also observed. A comparable amount of digitoxin did not affect ABCA8a mRNA expression in the liver. The results suggest that ABCA8 may play a role in digoxin metabolism in the liver.
Wakaumi
Michi
M
Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, Kawachi, Tochigi, Japan.
Ishibashi
Kenichi
K
Ando
Hitoshi
H
Kasanuki
Hiroshi
H
Tsuruoka
Shuichi
S
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000633:toxicity; D018076:DNA, Complementary / Q000096:biosynthesis; D004074:Digitoxin / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; C508626:Abca8b protein, mouse; D002316:Cardiotonic Agents; D018076:DNA, Complementary; D012333:RNA, Messenger; D004077:Digoxin; D004074:Digitoxin