Five synthetic compounds analogous to
pyrrolizidine alkaloids have been tested for toxicity in rats. These were the bis-N-ethylcarbamate
esters of synthanecines A, B, C and D (Compounds I-IV) and the bis-diethylphosphate
ester (V) of synthanecine A. The amino alcohol moiety in each of these had a single 5-membered heterocyclic ring in place of the pyrrolizidine amino alcohol (necine) moiety of natural
pyrrolizidine alkaloids. The toxicity of these compounds differed considerably. The synthanecine A
carbamate (I) was the most toxic, male and female rats being similarly susceptible. Like many hepatotoxic
pyrrolizidine alkaloids, a single dose of compound I caused acute centrilobular
necrosis of the liver, chronic hepatotoxicity involving the development of persistent giant hepatocytes, and
chronic lung injury. Compound III had similar actions but was less toxic. The synthanecine D
carbamate (IV) caused acute liver
necrosis but no chronic hepatotoxicity, whereas the synthanecine A
phosphate (V) had the opposite effect, with only chronic hepatotoxicity. The different toxic effects were related to the structure and metabolism of the compounds. Doses of compounds I, III and IV associated with a similar degree of acute hepatotoxicity led to similar levels of pyrrolic metabolites in the liver. Compound II, which was not hepatotoxic, gave very little liver
pyrrole. The liver level of pyrrolic metabolite from the
phosphate ester (V) decreased more rapidly than that from (I), and was not associated with acute toxicity.
Antimitotic activity, indicated by the appearance of bizarre giant cells, was shown by compounds capable of forming pyrrolic metabolites which were bifunctional
alkylating agents, but not by compound IV, which could only form a monofunctional
alkylating agent. Pretreatment with
phenobarbitone lowered the susceptibility of rats to compound I and greatly increased the liver level of pyrrolic metabolites associated with acute hepatotoxicity. Some rats given compounds I and III had kidney lesions primarily involving the glomerulus. The results confirm that toxic effects characteristic of many natural
pyrrolizidine alkaloids can be reproduced using simplified synthetic analogues, and that such toxicity is associated with pyrrolic metabolites.