Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues.
To see whether P-glycoprotein (PGP) expressed in renal brush-border membranes (BBM) could interact with compounds known as modulators of multidrug resistance (MDR), photoaffinity-labeling experiments were performed. A 145k-Da protein was photolabeled with [125I] iodoarylazidoprazosin, and this labeling was reduced in the presence of cyclosporin A (CsA) and PSC-833 (PSC). Interaction of CsA with PGP was further investigated by treating rats with daily subcutaneous injections of CsA (10 mg.kg-1.day-1). After this treatment, PGP expression levels were dramatically increased in renal BBM, intestine, liver, and many other tissues except the brain. This induction was a reversible process, since after cessation of CsA administration PGP levels declined to reach values similar to those of the control groups. The increase in PGP expression in the kidney was also detected in photolabeling experiments, suggesting the induction of a functional PGP. A higher dose of CsA (50 mg/kg) given as a bolus injection did not modify PGP expression] in renal BBM. These results demonstrate that CsA induces reversible overexpression of PGP in the rat. This may present significant relevance in the design of clinical trials using CsA as a chemosensitizing agent.
Jetté
L
L
Département de Chimie-Biochime, Université du Québec à Montréal, Quebec, Canada.
Beaulieu
E
E
Leclerc
J M
JM
Béliveau
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000345:Affinity Labels; D000818:Animals; D001386:Azides; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D011224:Prazosin / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C041552:azidoprazosin; C070272:valspodar; D011224:Prazosin