Differential Developmental and Tissue‐Specific Regulation of Expression of the Genes Encoding Three Members of the Flavin‐Containing Monooxygenase Family of Man, FMO1, FMO3 and FMO4

Abstract

. We present here the isolation of a cDNA for FMO3 of iiian. Thc sequcncc of this cDNA and the atnino acid sequcnce deduced from it differ substantially from those previously reported for this member of the FMO family of man. In addition, we have investigated, by quantitative KNase protection assays, the expression in several foetal and adult human tissues of genes encoding FMOl, FM03 and FM04. Our results demonstrate that, in the adult, FMOI is expressed in kidney hut not in livcr, whcrcas in the foetus it is expressed in both organs. The lack of expression of FA401 in adult hurnan liver is in marked contrast to the situation in other mammals, such as pig and rabbit, in which FMOl constitutvs ii major form of the enzyinc in the liver of the adult animal. The rnRNA encoding FMO3 is abundant in adult liver and i s also present, in low abundance, in some foetal tissues. Thus, FMOI and FMO3 are bnth subject to developmcntal and tissue-specific rcgulation, with a developnicntal switch in the expression of the genes taking place in the liver. FMO4 mRNA is present i n low abundancc in several foetal arid adult tissues and thus the corresponding gene appears to be expressed constitutively.Keyworcls: cDNA; sequence ; flavin-containing nionooxygcnases ; regulation: human.The microsomal flavin-containing rnonooxygenase (FMO) catalyscs the NADPH-dcpendent oxidativc tnetabolism of numerous foreign compounds including many therapeutic agents and pesticides (Ziegler, 1990(Ziegler, , 1993. FMO substrates are restricted to compounds that contain ii soft nucleophilic heteroatom as the sitc for oxygenation by the C4a-peroxyflavin fortn of the FAD prosthetic group. One such conipound is the simple dictary-derived aliphatic atnine trinicthylaminc. Oxidation of trimcthylamine to its N-oxide is mediated by FMO, and is subject to :I genetic polyinorphisrri in iniiii that results in 11 subpopulation with reduced trimethylainine N-oxidation capacity (A1 Waiz et al., 1987). Such individuals excrete relatively large amounts of triincthylatnine in thcir urine, sweat and breath, and exhibit a fishy body odour, characteristic of the associated disorder triinethylaminuria or fish-odour syndrome (Humbert et id., 1970; Shelley and Shelley, 19x4 The enzyrnic properties and catalytic riiechanisiii of FMO were c)riginally characterized using a hornogcneous protein prrparation froin pig liver (Ziegler and Mitchell, 1972). FMOs have subsequently been purified and characteriml from the livers of sevcral other species (Kiinura et al., 19x3; Sabourin ct al., 1084; Tynes aid Hodgson, 1985) und from rahbit and mouse lung (Williams et al., 1984; Tynes zt al., 1985). Observed diffexnccs in immunological cross-rcactivities, suhstrale prcfcrences and other physical properties between livcr and lung FMOs provided evidence for the existence of' multiplc forms of the enxymc (Williams et al., 1984; Tynes et al.. 1985Tynes et al.. , 1986; Poulsen ct d., 19x6). More reccntly, the isolation of cDNA clones that encode different forms of the enzyrne has confirnicd t...

Flavin-containing monooxygenases: mutations, disease and drug response

“…Of the FMOs involved in drug metabolism, FMO3 is the main form present in the adult human liver [12,13,32], which is not the case in other mammals investigated. The age at which the gene is switched on varies from birth to up to two years old, but by 10 months of age most individuals are expressing the enzyme [36].…”

“…Thus, in the adult human FMO1 makes no contribution to the hepatic metabolism of drugs. The lack of FMO1 expression in adult human liver [12,[31][32][33]36] is in contrast to all other mammals investigated, in which FMO1 represents a major hepatic form of the enzyme. LINE-1 elements upstream of the core liver promoter of FMO1 act as powerful transcription repressors, which might account for the silencing of the gene in the adult human liver [37].…”

“…FMO1 is, thus, likely to play an important role in the renal metabolism of drugs. The FMO1 gene is expressed in fetal human liver [12,[31][32][33]36], but its expression is extinguished just after birth [36]. Thus, in the adult human FMO1 makes no contribution to the hepatic metabolism of drugs.…”

“…In adult humans the main site of expression of FMO1 is the kidney [12,[31][32][33]. In this organ the amount of FMO1 [33] exceeds that of the total content of CYPs [34] and approaches that observed in the liver for the major hepatic CYP CYP3A4 [35].…”

Extrahepatic Metabolism of Carbamate and Organophosphate Thioether Compounds by the Flavin-Containing Monooxygenase and Cytochrome P450 Systems

“…Previous studies in our laboratory have observed that FMO1 catalyzed the sulfoxidation of carbamate and organophosphate pesticides much more efficiently than FMO3 (Schlenk et al, 2002;Furnes and Schlenk, 2004). In adult humans, FMO3 is the major liver isoform, and FMO1 primarily is found in kidney and intestines (Dolphin et al, 1996;Overby et al, 1997;Yeung et al, 2000). Thus, the contribution of the FMO system to hepatic organophosphate metabolism is thought to be modest.…”