Abstract
Reaction of an antihypotensive drug, etilefrin [α-{(ethylamino)methyl}-m-hydroxybenzyl alcohol], with nitrite under mildly acidic conditions produced N-nitrosoetilefrin [α-{(N-nitrosoethylamino)methyl}-m-hydroxybenzyl alcohol] (a mixture of syn and anti forms) (Iab) and diazo-N-nitrosoetilefrin [1-(4-diazo-3-oxo-1, 5-cyclohexadienyl-2-(N-nitrosoethylamino)ethanol] (a mixture of syn and anti forms) (IIab). Treatment of etilefrin with an equivalent amount of nitrite at pH 3 and 37°C for 4 h gave lab (yield, 30%) and IIab (yield, 5%). Treatment of eilefrin with 4 eq of nitrite under the same conditions gave Iab (23%) and IIab (53%). Compounds Iab IIab were each composed of two isomers due to the configuration of the N-nitroso group. While compound Iab was not mutagenic, compound IIab showed mutagenicity to Salmonella typhimurium TA98 and TA100 strains without metabolic activation. Specific mutagenic activity of IIab was 300 his+ revertant colonies for both TA98 and TA100 strains with a dose of 0.1μmol. Addition of a microsomal activation system little affected the activity. It is noteworthy that this orally administered drug can produce a direct-acting mutagen by reaction with nitrite, which is present in the digestive tract.
