Species differences in the stereoselectivity of N-oxygenation of N-ethyl-N-methylaniline in vitro.
The prochiral tertiary amine N-ethyl-N-methylaniline (EMA) is known to be stereoselectively N-oxygenated in the presence of hepatic microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin-containing monooxygenase ( FMO) enzyme system. In order to characterise this reaction further, the in vitro metabolism of EMA in the presence of hepatic microsomal preparations derived from a number of laboratory species has been examined. EMA N-oxide formation was stereoselective with respect to the (-)-S-enantiomer in the presence of microsomal preparations from all species examined, with the degree of selectivity decreasing in the order of rabbit > rat approximately LACA mouse approximately DBA/2Ha mouse > guinea-pig > dog. The enantiomeric composition of the metabolically derived EMA N-oxide appeared to be determined solely by the differential rate of formation of the two enantiomers as opposed to any differences in affinities for the substrate in its pro-R and pro-S conformations. The use of enzyme inhibitors, activators and inducers indicated that EMA N-oxide formation was predominantly mediated by FMO in the presence of rabbit hepatic microsomes and that these agents did not generally affect the stereochemical outcome of the biotransformation.[1]References
- Species differences in the stereoselectivity of N-oxygenation of N-ethyl-N-methylaniline in vitro. Hadley, M.R., Oldham, H.G., Camilleri, P., Damani, L.A., Hutt, A.J. Chirality. (1996) [Pubmed]
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