Mutagenicity of furoquinoline alkaloids in the Salmonella/microsome assay. Mutagenicity of dictamnine is modified by various enzyme inducers and inhibitors

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Abstract
Furoquinoline alkaloids are activated to mutagens by microsomal preparations of rat liver. The mutagenic effects decrease with the increasing number of methoxyl-substituents on the furoquinoline skeleton. After metabolic activation dictamnine, γ-fagarine and skimmianine exhibit strong mutagenicity in Salmonella typhimurium strains TA98 and TA100 and have comparatively little or no activity in the corresponding non-R-factor strains TA1538 and TA1535. This indicates that these compounds primarily act as frameshift mutagens. The activation capacity of the metabolizing mixture depends on the amount of microsomal protein. Pretreatment of male Wistar rats with phenobarbital (Pb) or 3-methylcholanthrene results in an increase in the metabolic capacity of the corresponding liver microsome preparations, Pb induction showing the greater effect. Various enzyme inhibitors, such as carbon monoxide, metyrapone, SKF-525A, 7,8-benzoflavone and methimazole, decrease the activation capacities of rat liver preparations, whereas 1,1,1-trichloro-propene-2,3-oxide has no effect. These results suggest that furoquinolines are activated to mutagenic metabolites by cytochrome-P-450 and cytochrome-P-448, and possibly by the flavin-containing monooxygenase.

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