Formation of a direct mutagen, diazo-N-nitrosoetilefrin, by interaction of etilefrin with nitrite.

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Abstract
Reaction of an antihypotensive drug, etilefrin [.alpha.-{(ethylamino)methyl}-m-hydroxybenzyl alcohol], with nitrite under mildly acidic conditions produced N-nitrosoetilefrin [.alpha.-{(N-nitrosoethylamino)methyl}-m-hydroxybenzyl alcohol] (a mixture of syn and anti forms) (lab) 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.degree.C for 4 h gave Iab (yield, 30%) and IIab (yield, 5%). Treatment of etilefrin with 4 eq of nitrite under the same conditions gave Iab (23%) and IIab (53%). Compounds Iab and 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 0.1 .mu.mol. 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.

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