alpha-Amanitin uptake into hepatocytes. Identification of hepatic membrane transport systems used by amatoxins.
1986; Elsevier BV; Volume: 261; Issue: 27 Linguagem: Inglês
10.1016/s0021-9258(18)67125-x
ISSN1083-351X
AutoresK D Kröncke, Gert Fricker, Peter J. Meier, W. Gerok, T Wieland, Gerhart Kurz,
Tópico(s)Toxin Mechanisms and Immunotoxins
ResumoHepatic transport studies with amatoxins, toxic bicyclic octapeptides from poisonous mushrooms of the genus Amanita were performed, using {(6'-0,1'-Ndi[3H]methyl)trp4)-a-amanitin and {(6'-O,l'-N-dimethyl)trp4)-~4-[3H]desmethyl)hyi3}-y-amanitin.Uptake into hepatocytes from rat liver was inhibited by taurocholate and antamanide.Photoaffinity labeling studies with isolated hepatocytes and basolateral plasma membranes, using the sodium salt of (7,7-azo-3a,l2a-dihydr0xy-58-[3~-~H]cholan-24-oyl)-2-aminoethanesulfonic acid demonstrated that the presence of a-amanitin decreased the labeling of the two sinusoidal bile salt-binding membrane polypeptides with the apparent molecular weights of 54,000 and 48,000.In basolateral plasma membrane vesicles amanitin uptake was temperature-dependent and could be stimulated 1.5 to 2-fold by an out to in Na+ gradient as compared to a K+ gradient or sucrose and 2 to 2.5-fold as compared to amanitin equilibration (overshoot).Kinetic studies proved saturability of amanitin uptake in the presence and absence of a Na+ gradient.Membrane transport could be inhibited by taurocholate, antamanide, phalloidin, prednisolone, and silybin, but not by penicillin G or thioctic acid.Hepatic uptake of amatoxins is mediated by the sinusoidal bile salt-transport systems which are also involved in the uptake of antamanide and phalloidin.This supports the concept of a multispecificity of hepatic transport systems for a wide variety of amphipathic molecules.Most accidental mushroom poisonings are caused by the toadstools of the genus Amanita, such as the green capped Amanita phalloides, the white colored Amanita verna, and Amanita virosa.The toxic compounds occurring in Amanita species are cyclic oligopeptides, including amatoxins, phallotoxins, and virotoxins (1-3).The amatoxins, bicyclic octapeptides, are the sole cause of lethal human poisoning.Toxicity of amatoxins is due to inhibition of RNA polymerases, preferentially RNA polymerase I1 (EC 2.7.7.6), thus blocking mRNA synthesis (4, 5).They exert their most dramatic toxic
Referência(s)