Altered expression and function of P-glycoprotein in dextran sodium sulfate-induced colitis in mice.
P-glycoprotein (P-gp), the product of the multiple drug resistance (mdr) gene, can actively pump toxic drugs out of cells, but its pathophysiologic role is not yet fully understood. In this study, we examined the expression of P-gp in dextran sodium sulfate (DSS)-induced colitis in mice. Eight-week-old Balb/c female mice were given drinking water containing 7% DSS ad libitum for 7 days. Mice receiving DSS were sacrificed on days 3, 5, and 7 for histopathologic study. Tissue samples were examined by hematoxylin and eosin (HE) staining, and immunostained against mdr, CD4+, CD8+, and B220+. RNA was isolated from the large intestine and the expression of mdr1a was determined by RT-PCR. The function of P-gp was evaluated by rhodamine123 efflux using the everted sac method. The induction of colitis in mice was confirmed by body weight changes, HE staining and immunohistological grading of the large intestine with reference to CD4+, CD8+, and B220+ after 7 days of treatment. Severe inflammation was observed in the large, but not the small, intestine on day 7. The expression of mdr1a in the large intestine was reduced on days 3, 5, and 7. In addition, the P-gp function and the expression of PXR were also reduced in the large intestine of DSS-treated mice on day 3. This reduction was consistent with the immunohistologic observations. The expression of the mdr1a gene was reduced before severe symptoms appeared. These results suggest that P-gp expression may be related to the pathology of colitis.
Iizasa
Hisashi
H
Department of Pharmaceutics, Kyoritsu College of Pharmacy, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512, Japan.
Genda
Naomi
N
Kitano
Tomohide
T
Tomita
Mikio
M
Nishihara
Kazuyo
K
Hayashi
Masahiro
M
Nakamura
Kayako
K
Kobayashi
Shizuko
S
Nakashima
Emi
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D016264:Dextran Sulfate