Evaluation in vitro of several pyrrolizidine alkaloid carcinogens: observations on the essential pyrrolic nucleus

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Abstract
Six compounds related to pyrrolizidine alkaloids have been subjected to an in vitro mammalian cell transformation test. Two hepatocarcinogenic alkaloids (retrorsine and monocrotaline) and one synthetic analogue (synthanecine A bis-N-ethylcarbamate) gave positive results while a non-toxic alkaloid (rosmarinine) was negative in the test. Positive results were also given by dehydroretronecine, a secondary pyrrolic alkaloid metabolite, and the closely related synthetic compound 2,3-bishydroxy-methyl-1-methylpyrrole. These observations lend support to the hypothesis that a simple alkylating pyrrole is the biologically active chemical agent derived from these alkaloids. The negative transformation response observed for the non-carcinogenic alkaloid rosmarinine establishes that the carcinogenic alkaloids are inducing transformation rather than simply selecting for spontaneous transformants. The mammalian-derived cells used in this study, unlike S.typhimurium, were capable of activating retrorsine in the absence of an auxiliary source of metabolising enzymes (S-9 mix).

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