Antimitotic activity of dehydroretronecine, a pyrrolizidine alkaloid metabolite, and some analogous compounds, in a rat liver parenchymal cell line.

The actions of 13 pyrrolic alcohols with similar chemical properties have been tested on cultured liver cells. Two, dehydroretronecine and dehydrosupinidine, were putative metabolites of hepatotoxic pyrrolizidine alkaloids; the remainder were synthetic. All were either mono- or bi-functional alkylating agents. Groups of cells were exposed to the compounds and were later stimulated to divide by changing the medium, then fixed, stained, and the proportions of cells in mitosis counted and compared with those in similarly treated control cells. Eleven compounds partially or completely inhibited cell division at concentrations of 10(-4) M or less. Bifunctional compounds, including dehydroretronecine and 2,3-bis-hydroxymethyl-1-methylpyrrole, had the highest antimitotic activity coupled with lowest cytotoxicity. The least chemically reactive compound, 3-hydroxymethyl-1-methylpyrrole, was neither antimitotic nor cytotoxic, whereas the monofunctional alkylating agents with highest reactivity, such as 3-hydroxymethyl-1,2-dimethylpyrrole, were the most toxic to the cells. The mitotic block occurred at a post-synthetic stage of the cell cycle, and affected cells could grow to a giant size.