Formation of a direct mutagen, diazo-N-nitrosoetilefrin, by interaction of etilefrin with nitrite.
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) (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 degrees 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 mumol. 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.
Kikugawa
K
K
Kato
T
T
Takeda
Y
Y
D002855:Chromatography, Thin Layer; D005039:Etilefrine / Q000031:analogs & derivatives* / Q000032:analysis* / Q000138:chemical synthesis / Q000633:toxicity; D009153:Mutagens / Q000138:chemical synthesis*; D009573:Nitrites / Q000032:analysis*; D009602:Nitrosamines / Q000138:chemical synthesis* / Q000633:toxicity; D010656:Phenylephrine / Q000031:analogs & derivatives*
D009153:Mutagens; D009573:Nitrites; D009602:Nitrosamines; C061098:diazo-N-nitrosoetilefrin; D010656:Phenylephrine; D005039:Etilefrine