Multiplicity and ligand selectivity

Historically, the FMO enzyme system was first characterized with regard to its substrate specificity and catalytic mechanism using the enzyme isolated in the 1970s from hog liver by Ziegler and associates.41 Molecular biology techniques have now revealed the existence of up to 13 FMO genes, only five of which are functional and expressed in all mammalian species examined to date.42 Compared to the P450s, FMO taxonomy is greatly simplified by the absence of gene family expansion, so, for example, there is only a single FMO1, as no subfamilies have been identified.43 The five active forms of the enzyme are termed FMO1-FMO5. These enzymes exhibit only 50-55% sequence homology, whereas species orthologs (i.e., rat FMO, human FMO1, dog FMO1, etc.) share 80-90% homology. Human FMO6 is inactive due to alternative splicing that results in a nonfunctional protein.44 Although five functional mammalian forms of the enzyme are recognized, in practice only two - FMO3 (major) and FMO1 (minor) - appear to be relevant to human drug metabolism.

Table 4 Ontogeny of major hepatic drug-metabolizing enzymes

Enzyme

Prenatal trimester 1 2

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