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.
SmithKline Beecham Pharmaceuticals, Tonbridge, Kent, England.
M R
MR
Hadley
H G
HG
Oldham
P
P
Camilleri
L A
LA
Damani
A J
AJ
Hutt
D000814:Aniline Compounds / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003578:Cytochrome-c Peroxidase / Q000378:metabolism; D004285:Dogs; D016166:Free Radical Scavengers / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006168:Guinea Pigs; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism
D000814:Aniline Compounds; D016166:Free Radical Scavengers; D018757:GABA Modulators; C010951:N-ethyl-N-methylaniline; D003578:Cytochrome-c Peroxidase; D008995:Monoamine Oxidase; D010634:Phenobarbital