The role of mdr2 in manganese-bilirubin induced cholestasis in mice.
The pathogenesis of manganese-bilirubin (Mn-BR) induced cholestasis has only been studied in rats and is associated with alteration in the hepatic homeostasis of cholesterol and phospholipids. Multidrug resistance-2 (mdr2) transporter, which mediates excretion of these lipids, is suggested to be involved in this phenomenon. The present study was undertaken to examine if Mn-BR induced cholestasis is reproducible in mice, then to clarify the role of mdr2 in its pathogenesis, using mice with disrupted mdr2 gene (mdr2 (-/-)). Results showed that Mn-BR combination decreased bile flow in mice. This reduction in bile flow was similar in mdr2 (-/-) and the wild type mdr2 (+/+). Furthermore, the change in biliary lipid excretion was comparable in both genotypes. These data indicate that Mn-BR induced cholestasis is reproducible in mice and provide evidence that mdr2 alteration is not a primary event in this form of cholestasis.
Akoume
Marie-Yvonne
MY
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Centre-ville, Que., Canada.
Tuchweber
Beatriz
B
Plaa
Gabriel L
GL
Yousef
Ibrahim M
IM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000494:pharmacology*; D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology*; D000818:Animals; D001663:Bilirubin / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced* / Q000235:genetics / Q000662:veterinary; D018432:Drug Resistance, Multiple; D005838:Genotype; D050356:Lipid Metabolism; D008297:Male; D020149:Manganese Poisoning / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D051381:Rats
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; C095122:multidrug resistance protein 3; D001663:Bilirubin