Cashman J R, Yang Z, Yang L, Wrighton S A
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California-San Francisco.
Drug Metab Dispos. 1993 May-Jun;21(3):492-501.
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.
补充了NADPH的成人肝脏微粒体催化了几种10-(N,N-二甲基氨基烷基)吩噻嗪的脂肪族叔胺的区域选择性N-氧化以及吩噻嗪硫原子的S-氧化。此外，在NADPH和成人肝脏微粒体存在的情况下，(+)-和(-)-4-溴苯基-1,3-氧硫杂环戊烷被转化为相应的S-氧化物。4-溴苯基-1,3-氧硫杂环戊烷的(+)和(-)对映体分别以低和高立体选择性转化为S-氧化物。对10-(N,N-二甲基氨基烷基)吩噻嗪N-氧化的生化机制研究表明，该反应由含黄素单加氧酶（形式II）催化，尽管细胞色素P-450 2D6也可能对N-氧化物的形成有贡献。氯丙嗪的S-氧化主要由细胞色素P-450 3A催化。10-(N,N-二甲基氨基烷基)吩噻嗪的S-氧化由多种细胞色素P-450催化，包括细胞色素P-450 2A6、2C8和2D6。(+)-4-溴苯基-1,3-氧硫杂环戊烷的S-氧化在一个可能依赖于两种肝脏单加氧酶系统的过程中产生顺式和反式非对映异构体的混合物。(-)-4-溴苯基-1,3-氧硫杂环戊烷在一个可能依赖于成人肝脏含黄素单加氧酶（形式II）的过程中几乎完全转化为反式S-氧化物。开发成人肝脏含黄素单加氧酶（形式II）和细胞色素P-450活性的区域和立体化学探针可能有助于最终的体外-体内相关性研究，但可能需要与目前用于动物单加氧酶的方法截然不同的方法。
