CYCLOSPORINE-A TREATMENT INDUCES OVEREXPRESSION OF P-GLYCOPROTEIN IN THE KIDNEY AND OTHER TISSUES

To see whether P-glycoprotein (PGP) expressed in renal brush-border me mbranes (BBM) could interact with compounds known as modulators of mul tidrug resistance (MDR), photoaffinity-labeling experiments were perfo rmed. A. 145-kDa protein was photolabeled with [I-125]iodoarylazidopra zosin, and this labeling was reduced in the presence of cyclosporin A (CsA) and PSC-833 (PSC). Interaction of CsA with PGP was fur ther inve stigated by treating rats with daily subcutaneous injections of CsA (1 0 mg . kg(-1). day(-1)). After this treatment, PGP expression levels w ere dramatically increased in renal BBM, intestine, liver, and many ot her tissues except the brain. This induction was a reversible process, since after cessation of CsA administration PGP levels declined to re ach values similar to those of the control groups. The increase in PGP expression in the kidney was also detected in photolabeling experimen ts, 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 i n renal BBM. These results demonstrate that CsA induces reversible ove rexpression of PGP in the rat. This may present significant relevance in the design of clinical trials using CsA as a chemosensitizing agent .