Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats

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.

Orellanine: From Fungal Origin to a Potential Future Cancer Treatment

“…A combination of animal studies and biopsies taken from poisoned patients have shown that orellanine acts on the proximal tubular cells of the kidney, with a significant degree of selectivity, even over other renal cells. , The selectivity of its uptake is poorly understoodwhile it has been suggested that it enters proximal tubular cells via an active, sodium independent transporter, this has yet to be confirmed or investigated further. It has also been suggested that orellanine is re-absorbed from the urine by a specific renal transporter, as the observed plasma half-life in rats was longer than what would be predicted for a molecule with similar physicochemical properties …”

“…As a group of compounds, orellanine and its metabolites have several properties that lend themselves to identification and quantification, by liquid chromatographic methods in particular. While orellanine itself lacks a fluorophore, its reduced metabolite orelline produces a distinctive turquoise fluorescence (excitation wavelength 400 nm, emission wavelength 450 nm) ,,− and is readily formed under a range of conditions, including when exposed to UV light. ,− ,,, This can be explained by the reduction of the N -oxides, which enables the necessary electron spin transitions via keto–enol tautomerism, a phenomenon seen across a range of 3,3′-dihydroxy bipyridines , (Figure ). …”

“…Despite this, there are a few challenges associated with orellanine analysis. The first is that while analysis of plasma levels is relatively straightforward, ,− , extraction from renal tissue samples is more challenging, with the toxin exhibiting reduced solubility in the intracellular environment. , Given orellanine’s rapid plasma clearance and prolonged tissue retention, such tissue sample assays ,, have greater applications in a diagnostic setting than the more commonly reported plasma extractions. ,,− , Likewise, methods to quantitatively assess and compare the uptake of orellanine or orellanine derivatives in proximal tubular cells and ccRCC cells would have value in assessing the selectivity of orellanine-based cancer treatments.…”

“…Another complication is that there is no consensus as to whether derivatization is necessary to enable their MS analysis. ,, When orellanine is tested or analyzed in biological samples, this at first appeared not to be a major issue as the acidic solvent conditions used ensured that there was minimal intact glucoside present during analysis. However, during pharmacokinetic studies carried out by Najar et al, a cluster of apparent orellanine metabolites were detected via LC-MS analysis in rat plasma samples following orellanine dosing. These metabolites had shorter retention times, eluting after 4 min vs 5.2 min for orellanine.…”

Venom Toxins as Potential Targeted Therapies

“…This Special Issue of Toxins includes three recent advanced research studies related to bee venoms as potential medicinal therapy in different aspects [1,2,3]. Furthermore, recent advances in bioactive molecules finding from frog skins, mushroom and venom/toxin/immunotoxins for targeted cancer therapy and immunotherapy are discussed [4,5,6,7,8]. The discussion on using novel disease-specific venom-based protein/peptide/toxin along with currently available FDA approved drugs as combinatorial treatment, such as a family of novel types of antimicrobial agents, were also encouraged to be discussed in these contexts.…”