Entero-bacterial Formation of Cyclohexylamine in Rats Ingesting Cyclamate

Abstract

1. Groups of rats were given cyclamate (100 mg/day) in the drinking water for 6–15 months; of 26 animals, 24 became ‘converter rats’ within 1–7 months, excreting 1 to 70% of the dose as cyclohexylamine.

2. Ability of converter rats to metabolize cyclamate was lost in 1 to 2 weeks after withdrawal of cyclamate, but was regained 1 week after resumption of cyclamate treatment. This ability was lost when neomycin or gentamicin was added to the drinking water in addition to cyclamate and was then regained after 10–58 days according to the dose of the antibiotic. Neomycin, polymyxin, or gentamicin added to faeces incubations inhibited or blocked cyclohexylamine formation at low doses, suggesting that the micro-organism(s) responsible for the conversion may belong to aerobic, gram-negative species.

3. Normal rats given 100 mg of converter rat faeces intragastrically, became converter rats in 1 to 2 weeks under chronic cyclamate treatment. No conversion was observed in 1.5 months when the faecal organisms were killed by heat, or when faeces from preconverter or normal rats were used.

4. In rats followed from the normal to the converter phase, significant changes of faecal microflora were not detected with respect to clostridia, enterococci, lactobacilli, bacteroides, E. coli and proteus.

5. Normal and preconverter rats given single oral doses of cyclamate excreted more than half the dose in the faeces, and metabolized less than 0.2% of a dose of cyclamate to cyclohexylamine. In converter rats accumulation of both compounds was suggested to have occurred in the tissues during the long-term treatment. Intraperitoneal injection of [¹⁴C]cyclamate, instead of oral, resulted in negligible formation of [¹⁴C]cyclohexylamine in converter rats.