Relationship between P-glycoprotein expression and cyclosporin A in kidney. An immunohistological and cell culture study.
P-glycoprotein (P-gp), encoded in humans by the mdr-1 gene, acts physiologically as an efflux pump to expel hydrophobic substances from cells. This glycoprotein is closely related to multidrug resistance in tumor cells and can be modulated by cyclosporin A (CsA). We investigated the relationship between CsA and P-gp in 52 renal allograft biopsies and in cultures of Madin-Darby canine kidney (MDCK) renal tubule cells to determine whether the intrarenal accumulation of CsA or chronic stimulation with the drug modified the expression of P-gp. Expression of P-gp and CsA was analyzed by immunohistochemistry. Immunostaining was evaluated semiquantitatively. Modulation of P-gp in MDCK cells after chronic stimulation with CsA for 7, 30, and 60 days was analyzed by flow cytometry. P-gp and CsA immunostaining in renal post-transplant biopsies showed considerable overlap in all cases (Spearman's test, r = 0.577, P < 0.001). After 7 days in vitro, the number of cells expressing P-gp increased progressively; a further increase in mean fluorescence was found after 60 days (P < 0.001, Student's t-test). Our findings suggest that in non-neoplastic cells, CsA may stimulate P-gp as a mechanism of detoxification. Individual differences in the adaptive responses to glycoprotein may be responsible for the appearance of nephrotoxicity or a CsA-resistant rejection reaction in cases of overexpression on lymphocytes and macrophages.
Department of Pathology, University Hospital and School of Medicine, University of Granada, Granada, Spain.
R
R
García del Moral
F
F
O'Valle
M
M
Andújar
M
M
Aguilar
M A
MA
Lucena
J
J
López-Hidalgo
C
C
Ramírez
M T
MT
Medina-Cano
D
D
Aguilar
M
M
Gómez-Morales
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects* / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016572:Cyclosporine