Cyclosporin a treatment induces overexpression of p-glycoprotein in
the kidney and other tissues.
Jett[acute]e, Lucie, Edith Beaulieu, Jean-Marie Leclerc, and Richard
B[acute]eliveau.
Laboratoire de Membranologie, Groupe de Recherche en
Bioth[acute]erapeutique Mol[acute]eculaire, D[acute]epartement de
Chimie-Biochimie, Universit[acute]e du Qu[acute]ebec [grave]a
Montr[acute]eal, C.P. 8888, Succursale A, Montr[acute]eal,
Qu[acute]ebec, Canada, H3C 3P8, H[circumflex]opital Ste-Justine,
Montr[acute]eal, Qu[acute]ebec, Canada
APStracts 2:0197F, 1995.
To see whether P-gp expressed in renal brush border membranes (BBM)
could interact with compounds known as modulators of multidrug
resistance (MDR), photoaffinity labeling experiments were performed.
A 145-kDa protein was photolabeled with [125I]iodoarylazidoprazosin
(IAAP) and this labeling was reduced in the presence of cyclosporin A
(CsA) and PSC 833 (PSC). Interaction of CsA with P-gp was further
investigated by treating rats with daily subcutaneous (s.c.)
injections of CsA (10 mg/(kg.day)). Following this treatment, P-gp
expression levels were dramatically increased in renal BBM,
intestine, liver, and many other tissues, except the brain. This
induction was a reversible process since following cessation of CsA
administration, P-gp levels declined to reach values similar to those
of the control groups. The increase in P-gp expression in the kidney
was also detected in photolabeling experiments, suggesting the
induction of a functional P-gp. A higher dose of CsA (50 mg/kg) given
as a bolus injection did not modify P-gp expression in renal BBM.
These results demonstrate that CsA induces reversible overexpression
of P-gp in the rat. This may present significant relevance in the
design of clinical trials using CsA as a chemosensitizing agent.
Received 18 May 1995; accepted in final form 27 October 1995.
APS Manuscript Number F157-5.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 November 95