title: Stereo- and regioselective N- and S-oxidation of tertiary amines and sulfides in the presence of adult human liver microsomes.
abstract: Adult human liver microsomes supplemented with NADPH catalyzed the regioselective N-oxygenation of the aliphatic tertiary amine and S-oxidation of the phenothiazine sulfur atom of several 10-(N,N-dimethylaminoalkyl)phenothiazines. In addition, (+)- and (-)-4-bromophenyl-1,3-oxathiolane were converted to the corresponding S-oxides in the presence of NADPH and adult human liver microsomes. The (+) and (-) enantiomers of 4-bromophenyl-1,3-oxathiolane were converted to the S-oxides with low and high stereoselectivity, respectively. Studies on the biochemical mechanism for N-oxygenation of 10-(N,N-dimethylaminoalkyl)phenothiazines suggested that this reaction was catalyzed by the flavin-containing monooxygenase (form II), although cytochrome P-450 2D6 may also have contributed to N-oxide formation. S-Oxidation of chlorpromazine was catalyzed mainly by cytochrome P-450 3A. S-Oxidation of 10-(N,N-dimethylaminoalkyl)phenothiazines was catalyzed by a number of cytochromes P-450, including cytochromes P-450 2A6, 2C8, and 2D6. S-Oxygenation of (+)-4-bromophenyl-1,3-oxathiolane produced a mixture of the cis- and trans diastereomers in a process probably dependent on both hepatic monooxygenase systems. (-)-4-Bromophenyl-1,3-oxathiolane was converted almost exclusively to the trans-S-oxide in a process likely dependent on the adult human liver flavin-containing monooxygenase (form II). Development of regio- and stereochemical probes of adult human liver flavin-containing monooxygenase (form II) and cytochromes P-450 activity may be useful for eventual in vitro-in vivo correlations, but may require approaches quite distinct from that currently used for animal monooxygenases.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California-San Francisco.
authors.forename: J R
authors.initials: JR
authors.lastname: Cashman
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: S A
authors.initials: SA
authors.lastname: Wrighton
mesh_terms: D000293:Adolescent; D000328:Adult; D000588:Amines / Q000378:metabolism*; D000963:Antimetabolites / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005415:Flavins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D010087:Oxides / Q000378:metabolism; D013237:Stereoisomerism; D013440:Sulfides / Q000378:metabolism*
chemical_list: D000588:Amines; D000963:Antimetabolites; D005415:Flavins; D010087:Oxides; D013440:Sulfides; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases