Pathogenesis of hepatic necrosis caused by amanitin-albumin conjugate

Abstract

The peptides amanitins are the most powerful toxins of the toadstool Amanita phalloides ¹. Their cytopathic effect is due to inhibition of eucaryotic RNA-polymerase B (for reviews see Refs. 2 and 3). The low molecular weight of these toxic peptides (about 900) accounts for their lack of antigenic power. In order to obtain an immune response against these toxins, some years ago an attempt was made to render β-amanitin antigenic by conjugating it with rabbit serum albumin⁴. The water soluble carbodiimide ethyl-CDI was employed as the coupling agent. An unexpected increase was found in the toxicity of β-amanitin after conjugation. The LD₅₀ of β-amanitin is 0.4 µmol/kg in the mouse and after conjugation this decreases several times. Mice injected with a lethal dose of the conjugate died of an hepatic necrosis morphologically different from that observed following α-amanitin or β-amanitin administration. In mice killed by amanitin-albumin conjugates, ascites is often observed and the livers appear greatly enlarged and dark red. Histologic examination shows that sinusoidal spaces are extremely dilated. On the contrary in mice killed by free amanitin, liver congestion is rare and ascites is never observed.