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Tuesday, October 21, 2008

2001 FMO Paper : Study on Human FMO1 and FMO3 development. FMO1 the main hepatic form before birth. FMO3 after birth.

Human Hepatic Flavin-Containing Monooxygenases 1 (FMO1) and 3 (FMO3) Developmental Expression.

KOUKOURITAKI, SEVASTI B.; SIMPSON, PIPPA; YEUNG, CATHERINE K.; RETTIE, ALLAN E.; HINES, RONALD N.Departments of Pediatrics and Pharmacology and Toxicology, Birth Defects Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, U.S.A. [S.B.K., R.N.H.]; Center for Applied Research and Evaluation, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, U.S.A. [P.S.]; and Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, U.S.A. [C.K.Y., A.E.R.]

Received June 18, 2001; accepted September 26, 2001.

Correspondence: Ronald N. Hines, Ph.D., Medical College of Wisconsin, Department of Pediatrics, Birth Defects Research Center, 8701 Watertown Plank Rd., Milwaukee WI 53226-4801, U.S.A.; e-mail: rhines@mcw.edu

Full text at http://www.pedresearch.org


Main points:
The flavin-containing monooxygenases (FMOs) are important for the metabolism of numerous therapeutics and toxicants.
FMO is expressed in 6 ways in humans (FMO1-FMO6). FMO3 is the main liver isoform in humans after birth.
FMO1 expression was highest in the embryo liver.
Low levels of FMO3 expression also were detectable in the embryo, but not in the fetus.
The onset of FMO3 expression was highly variable, with most individuals failing to express this isoform during the neonatal period.
FMO3 was detectable in most individuals by 1-2 y of age and was expressed at intermediate levels until 11 y
A gender-independent increase in FMO3 expression was observed from 11 to 18 y of age.
2- to 20-fold interindividual variation in FMO1 and FMO3 protein levels were observed, depending on the age bracket.

Inefficient FMO3 function (or FMO3 overload in secondary TMAU) is the reason for the diagnosis of Trimethylaminuria (TMAU). This 2001 paper concludes that FMO1 is the main form of FMO enzyme in the liver (hepatic) before birth, and that full expression of FMO3 does not fully develop until as long as 18 years of age (actually they only investigated up until age 18, and speculate it could in theory be older, but this does not include mutant copies which are greatly limited by default). This may explain why official TMAU sites mention a type of TMAU called 'transient childhood TMAU'. There are many interesting points in the paper. Not least that there was a 2-20 fold difference in expression of the enzyme at different age brackets. Also there was a gender difference in increased expression in the 11-18 year old group.
The flavin-containing monooxygenases (FMOs) are important for the metabolism of numerous therapeutics and toxicants. Six mammalian FMO genes (FMO1-6) have been identified, each exhibiting developmental and tissue- and species-specific expression patterns. Previous studies demonstrated that human hepatic FMO1 is restricted to the fetus whereas FMO3 is the major adult isoform. These studies failed to describe temporal expression patterns, the precise timing of the FMO1/FMO3 switch, or potential control mechanisms. To address these questions, FMO1 and FMO3 were quantified in microsomal fractions from 240 human liver samples representing ages from 8 wk gestation to 18 y using Western blotting. FMO1 expression was highest in the embryo (8-15 wk gestation; 7.8 +/- 5.3 pmol/mg protein). Low levels of FMO3 expression also were detectable in the embryo, but not in the fetus. FMO1 suppression occurred within 3 d postpartum in a process tightly coupled to birth, but not gestational age. The onset of FMO3 expression was highly variable, with most individuals failing to express this isoform during the neonatal period. FMO3 was detectable in most individuals by 1-2 y of age and was expressed at intermediate levels until 11 y (12.7 +/- 8.0 pmol/mg protein). These data suggest that birth is necessary, but not sufficient for the onset of FMO3 expression. A gender-independent increase in FMO3 expression was observed from 11 to 18 y of age (26.9 +/- 8.6 pmol/mg protein). Finally, 2- to 20-fold interindividual variation in FMO1 and FMO3 protein levels were observed, depending on the age bracket.
http://www.pedresearch.org/pt/re/pedresearch/fulltext.00006450-200202000-00018.htm

The paper also has a good explanation about FMO and its role. Particularly that FMO3 is the main isoform in the liver of adult humans, but FMO1 is the main isoform in the intestine and kidneys.

The FMOs (EC 1.14.13.8) are important for the NADPH-dependent oxidative metabolism of a wide variety of compounds containing nucleophilic nitrogen-, sulfur-, selenium-, and phosphorous-heteroatoms Examples of known substrates of relevance to pediatric therapeutics include the antipsychotic chlorpromazine, the antihistaminics promethazine and brompheniramine, the H2-receptor antagonists cimetidine and ranitidine, and the gastroprokinetic agent itopride. However, given the prevalence of nitrogen- and sulfur-heteroatoms in medicinals, this short list is likely a gross underestimate of FMO's contribution to pediatric drug disposition. Environmental agents of particular concern include several thioether-containing organophosphorous pesticides, the carcinogen 2-aminofluorene, and the neurotoxicants nicotine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Finally, a few dietary and/or endogenous FMO substrates have been identified, including trimethylamine, a break-down product of dietary choline, cysteamine, methionine, and several cysteine-S-conjugates

Unlike the numerous cytochrome P450-dependent monooxygenases, there are only six mammalian FMO enzymes, each encoded by a distinct gene located on the long arm of human chromosome 1. As such, the FMO are considered more versatile with regard to substrate specificity than the cytochrome P450-dependent monooxygenases, a feature partly attributable to the FMO's unique catalytic mechanism. FMO species- and tissue-dependent expression has been well documented and within a given species and tissue, gender- and ontogenic-associated factors also may affect FMO expression. Finally, genetic variability within the FMO locus also influences expression.

Several studies have documented significant changes in the expression of xenobiotic metabolizing enzymes during development. FMO1 is the major hepatic isoform in most mammals examined to date, with the exceptions of the adult human and the adult female mouse where FMO3 is the predominant isoform. FMO1 is expressed at relatively high levels in human fetal liver and also represents the major FMO enzyme in the adult human and rabbit intestine and kidney. Thus, human FMO1 and FMO3 are subject to developmental and tissue-specific regulation, with a temporal switch in the hepatic expression of the two genes occurring some time after birth.

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