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.