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.
Hadley
M R
MR
SmithKline Beecham Pharmaceuticals, Tonbridge, Kent, England.
Oldham
H G
HG
Camilleri
P
P
Damani
L A
LA
Hutt
A J
AJ
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