Pancreatic and nephrotoxicity of immunomodulator compounds

Toxicology Letters
T G Hammond, C N Kind

Abstract

Increasing clinical experience of FK 506 in transplantation therapy has revealed a number of potentially restrictive adverse effects associated with its use. The mechanisms of action underlying 2 prominent toxic effects of FK 506, namely diabetogenesis and renal dysfunction, were investigated. A simple model system based on the effect of FK 506 on isolated rat pancreatic islets was utilised to study the relationship between inhibition of insulin biosynthesis, inhibition of interleukin 2 (IL-2) activation and FK binding protein (FKBP-12) binding of FK 506 and a number of FK 506 analogues. Results indicate that the action of these compounds on inhibition of insulin biosynthesis (and by implication, diabetogenesis) may be related to their immunosuppressive potential. Observations on the FK 506-induced release of endothelin-1 from isolated rat kidney mesangial cells suggest that this cell may be an important target associated with the nephrotoxic potential of the drug, and that this action may be mediated via the FKBP.

References

Dec 1, 1992·Transplantation·A MoutabarrikS Takahara
May 1, 1992·Transplantation·R V BundickE Wells
Jun 1, 1990·Kidney International·V KonR L Hoover
Jan 1, 1993·Journal of Cardiovascular Pharmacology·Y TakedaR Takeda
May 1, 1994·The Journal of Toxicological Sciences·Y HiranoH Noguchi
May 1, 1995·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·M Winkler, U Christians
Jan 1, 1993·Current Opinion in Nephrology and Hypertension·M S Simonson, M J Dunn

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Citations

Mar 28, 1998·Japanese Journal of Pharmacology·J UchidaT Kishimoto
Oct 23, 2009·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Jul 23, 1999·Renal Failure·W F Finn

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