The poisonous effect of the distaff thistle is well documented in history. The plant growing in the Mediterranean region was often used for suicide or murder. Examples of accidental poisoning are documented in Italy and Algeria in 1955 and 1975 respectively, where children have eaten parts of the plant. Although Ed Lefranc isolated Atractyloside in 1868 from Atractylis gummifera, the structure was identified 100 years later.
Chemistry
Atractyloside is a hydrophilic glycoside. A modified glucose is linked to the hydrophobic diterpene atractyligenin by a β1-glycosidic bond. A carboxyl group is positioned at the C4 position in the axial position. The glucose part is esterified with isovaleric acid on the C2' atom, and sulfuric acid on the C3' and C4' atoms. By hydrolysis a molecule of D--glucose, isovaleric acid, atractyligenin, and two molecules of sulfuric acid could be obtained. The two sulfate groups and the carboxyl group in ATR are in a deprotonated form under physiological conditions. Thus, ATR is triple negatively charged. A modified variant of the atractylenolide carries an additional carboxyl group at the C4 atom of the atractyligenin, which is then referred to as carboxy-atractyloside, sometimes referred to as "gummiferin".
Mechanism of action
In biochemical studies of mitochondria, the effect of atractyloside on the ADP/ATP transport was recognized even before the actual transporter was identified. ATR or CATR bind to the ADP/ATP translocase, which is located on the inner mitochondrial membrane. ATR binds competitively to the translocase competitive up to a concentration of 5 mmol while CATR binds in a non-competitive manner. As a result, the exchange of ADP and ATP is no longer carried out and the cell dies due to lack of energy. The chemical structure and charge distribution of atractyloside is similar to that of ADP: the sulfate groups correspond to the phosphate groups, the glucose part corresponds to the ribose part, and the hydrophobic atractyligenine residue corresponds to the hydrophobic purine residue of ADP. The carboxyl group on the C4 atom of the atractyligenin is important for toxicity. If this is reduced to a hydroxyl group, the substance becomes non-toxic. Modification of any of the sulfate groups renders the compound non-toxic. On the other hand, the free hydroxy group on the C6 atom of the glucose moiety can be modified without loss of compound potency.
Poisoning
The mean lethal dose in rats is for ATR 143 mg/kg, for CATR 2,9 mg/kg.
