The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression.
The flavin-containing monooxygenase (FMO) has been characterized in several mammalian species, including human. The FMO forms a stable NADP(H)- and oxygen-dependent 4 alpha-hydroperoxy flavin enzyme intermediate in the absence of an oxygenatable substrate. As such, substrate specificity appears to be controlled by access to this stabilized intermediate, resulting in this enzyme's ability to metabolize a wide variety of xenobiotics. These include tertiary and secondary alkyl- and arylamines, many hydrazines, thiocarbamides, thioamides, sulfides, disulfides, thiols, and other soft nucleophiles. Although some of these compounds are oxidized to less active derivatives, several examples of metabolic activation to potentially toxic intermediates also exist. Mercapto-pyrimidines and thiocarbamides, for example, appear to be activated predominantly by FMO. Thus, this enzyme system may play an important role in the early steps of chemical toxicity. Often, the contribution of FMO to the metabolism of a given compound can be assessed by its unique stereoselectivity relative to other oxygenases. For example, the cytochromes P450 oxidize (S)-nicotine to a mixture of cis- and trans-N-1'-oxides. In contrast, (S)-nicotine is oxidized by human FMO3 exclusively to the trans-N-1'-oxide. With the purification and cloning of FMO from multiple tissues and species it became apparent that more than one FMO exists. Further, there are considerable tissue- and species-specific differences in FMO expression that likely contribute to observed differences in detoxication competency and toxicant susceptibility.
Hines
R N
RN
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201.
Cashman
J R
JR
Philpot
R M
RM
Williams
D E
DE
Ziegler
D M
DM
D000818:Animals; D005415:Flavins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D010105:Oxygenases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013237:Stereoisomerism; D013379:Substrate Specificity; D015262:Xenobiotics / Q000378:metabolism*
D005415:Flavins; D015262:Xenobiotics; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)