Dehydration of alkyl- and arylaldoximes as a new cytochrome P450-catalyzed reaction: mechanism and stereochemical characteristics.
The Z isomers of benzaldoxime and 4-(hexyloxy)benzaldoxime were dehydrated into the corresponding nitriles in the presence of rat liver microsomes and NADPH or dithionite. Their E isomers remained unchanged under identical conditions. Alkylaldoximes, like phenylacetaldoxime and heptanaldoxime, are also dehydrated under these conditions, the alkylaldoximes being more rapidly transformed than the arylaldoximes. A genetically well-defined P450 expressed in yeast, P450 3A4, the major P450 isozyme in human liver, was also found to be catalytically active for dehydration of (Z)-benzaldoxime. All these reactions were found to be catalyzed by P450 Fe(II) as they required the use of intact microsomes in the presence of NADPH or dithionite and were strongly inhibited by O2 and CO as well as by classical P450 inhibitors. A P450 complex characterized by a Soret peak at 442 nm was detected during these reactions; its disappearance was found to be concomitant with the consumption of the aldoxime and the formation of the corresponding nitrile. (E)-benzaldoximes and all the studied ketoximes failed to give such complexes with P450 Fe(II). On the basis of these results, a possible mechanism for this new P450 reaction is proposed. It involves a P450 Fe(II)<--N(OH)=CHR complex as a key intermediate and a charge transfer from P450 Fe(II) to the aldoxime C=N bond which results in a cleavage of the aldoxime N-O bond.
Boucher
J L
JL
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, URA 400, Université Paris V, France.
Delaforge
M
M
Mansuy
D
D
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D003681:Dehydration; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism; D010091:Oximes / Q000737:chemistry / Q000378:metabolism*; D010100:Oxygen; D051381:Rats; D017207:Rats, Sprague-Dawley; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D014867:Water
D009570:Nitriles; D010091:Oximes; D014867:Water; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D010100:Oxygen