Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats.

Deman Najar,Kerstin Ebefors,Jenny Nyström,Carina Sihlbom,Annika Thorsell,Börje Haraldsson

doi:10.3390/toxins10080333

Abstract

Orellanine is a nephrotoxin found in mushrooms of the Cortinarius family. Accidental intake of this substance may cause renal failure. Orellanine is specific for proximal tubular cells and could, therefore, potentially be used as treatment for metastatic renal cancer, which originates from these cells. However, more information is needed about the distribution and elimination of orellanine from the body to understand its potential use for therapy. In this study, 5 mg/kg orellanine (unlabeled and 3H-labeled) was injected intravenously in rats (Wistar and Sprague Dawley). Distribution was measured (Wistar rats, n = 10, n = 12) using radioluminography and the highest amount of orellanine was found in the kidney cortex and bladder at all time-points investigated. The pharmacokinetic properties of orellanine were investigated using LC-MS/MS and β-scintillation to measure the amount of orellanine in plasma. Three groups of rats were investigated: control rats with intact kidneys (n = 10) and two groups with bilateral renal artery ligation (n = 7) where animals in one of these groups were treated with peritoneal dialysis (n = 8). Using LC-MS/MS, the half-life of orellanine was found to be 109 ± 6 min in the controls. In the groups with ligated renal arteries, orellanine had a half-life of 756 ± 98 min without and 238 ± 28 min with dialysis. Thus, orellanine was almost exclusively eliminated by glomerular filtration as well as by peritoneal dialysis.

Highlights

Orellanine is a natural toxin found in the Cortinarius family of mushrooms found in NorthAmerica and in Europe
At all time-points, the highest concentration of orellanine was found in the urinary bladder and the kidney cortex
We have shown in an earlier paper that orellanine toxicity extends to the renal carcinoma cells in vitro and to human renal cell carcinomas tumors on rats [8], which indicates that orellanine could have a future as an anti-renal cancer treatment

Summary

Introduction

Orellanine is a natural toxin found in the Cortinarius family of mushrooms found in North. Its selective renal toxicity was recognized already in the 1950s [1]. Several people suffer from renal damage ranging from reduced to complete loss of renal function by accidentally ingesting the mushroom and there is still no specific antidote to orellanine poisoning. It is well known that orellanine targets the tubular epithelium [2,3], but the toxicological properties and mechanisms are still not fully known. Several potential mechanisms have been described and all of them point towards oxidative stress [3,4,5,6].

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