| | |  | | | | Record from Web of Science® | | | | | | |
| THE IMMUNOSUPPRESSIVE AND TOXIC EFFECTS OF FK-506 ARE MECHANISTICALLY RELATED - PHARMACOLOGY OF A NOVEL ANTAGONIST OF FK-506 AND RAPAMYCIN |
|
|
| Author(s): DUMONT FJ, STARUCH MJ, KOPRAK SL, SIEKIERKA JJ, LIN CS, HARRISON R, SEWELL T, KINDT VM, BEATTIE TR, WYVRATT M, SIGAL NH |
| Source: JOURNAL OF EXPERIMENTAL MEDICINE Volume: 176 Issue: 3 Pages: 751-760 Published: SEP 1 1992 |
| Times Cited: 196 References: 40 |
| Abstract: FK-506 inhibits Ca2+-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex. |
| Document Type: Article |
| Language: English |
Addresses:
1. MERCK SHARP & DOHME LTD, DEPT IMMUNOL, RAHWAY, NJ 07065 USA
2. MERCK SHARP & DOHME LTD, DEPT BIOCHEM, RAHWAY, NJ 07065 USA
3. MERCK SHARP & DOHME LTD, DEPT BASIC MED CHEM, RAHWAY, NJ 07065 USA
4. MERCK SHARP & DOHME LTD, DEPT SAFETY ASSESSMENT, W POINT, PA 19486 USA |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 |
| Subject Category: Immunology; Medicine, Research & Experimental |
| IDS Number: JK427 |
| ISSN: 0022-1007 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |