Antidotal effect of cyclosporine A against alpha-amanitin toxicity in CD-1 mice, at clinical relevant doses

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Garcia, J (Author) Other; Carvalho, A (Author) Other; das Neves, RP (Author) Other; Malheiro, R (Author) Other; Rodrigues, DF (Author) Other; Figueiredo, PR (Author) Other; Bovolini, A (Author) Other; duarte, ja (Author) FADEUP; Costa, VM (Author) Other; Felix Carvalho (Author) FFUP

Journal

Title: Food and Chemical Toxicology

Vol. 166

ISSN: 0278-6915

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-00W-RR7

DOI: 10.1016/j.fct.2022.113198

Abstract (EN): Amanita phalloides is one of the most toxic mushrooms worldwide, being responsible for the majority of human fatal cases of mushroom intoxications. alpha-Amanitin, the most deleterious toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and renal failure. Herein, we used cyclosporine A after it showed potential to displace RNAP II alpha-amanitin in silico. That potential was not confirmed either by the incorporation of ethynyl-UTP or by the monitoring of fluorescent RNAP II levels. Nevertheless, concomitant incubation of cyclosporine A with alpha-amanitin, for a short period, provided significant protection against its toxicity in differentiated HepaRG cells. In mice, the concomitant administration of alpha-amanitin [0.45 mg/kg intraperitoneal (i.p.)] with cyclosporine A (10 mg/kg i.p. plus 2 x 10 mg/kg cyclosporine A i.p. at 8 and 12 h post alpha-amanitin) resulted in the full survival of alpha-amanitin-intoxicated mice, up to 30 days after the toxin's administration. Since alpha-amanitin is a substrate of the organic-anion-transporting polypeptide 1B3 and cyclosporine A inhibits this transporter and is a potent anti-inflammatory agent, we hypothesize that these mechanisms are responsible for the protection observed. These results indicate a potential antidotal effect of cyclosporine A, and its safety profile advocates for its use at an early stage of alpha-amanitin intoxications.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13