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Thursday, July 10, 2008

2005 paper : variations in fmo3 function with polymorphic genes

With bloodborne odors, presumably one or more of the enzymes in the body are past saturation point for some reason (whether excess load or a genetic weakness or a combination, or other reason). One of the most likely enzyme candidates for bloodborne odors is the FMO family of enzymes (in humans, mostly FMO3).

The flavin-containing monooxygenases (FMOs) are a family of NADPH and oxygen-dependent microsomal enzymes involved in the oxidative metabolism of many nucleophilic nitrogen-, sulfur- and phosphorous-containing drugs and toxicants. They are important for xenobiotic metabolism. FMO3, the predominant FMO enzyme in human adult liver, exhibits significant interindividual variation that is poorly understood.

This 2005 paper was written by a group of Researchers at the Departments of Pediatrics and Pharmacology/Toxicology, Medical College of Wisconsin, Milwaukee. They tested the DNA from 201 Hispanic-American (Mexican descent), 201 African-American, and 200 non-Latino White (northern European descent) subjects to identify common FMO3 genetic variants and determine their potential for contributing to interindividual differences in FMO3 expression. Seven common (>1%) promoter region haplotypes were inferred in one or more of the study populations that differed in estimated frequency among the groups. Haplotype 2 resulted in an 8- fold increase in promoter activity, while haplotype 8 and 15 exhibited a near complete loss of activity.

Discovery of Novel Flavin-Containing Monooxygenase 3 (FMO3) Single Nucleotide Polymorphisms and Functional Analysis of Upstream Haplotype Variants

Sevasti B. Koukouritaki, Mark T. Poch, Erwin T. Cabacungan, D. Gail McCarver, and Ronald N. Hines
Departments of Pediatrics and Pharmacology/Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA 53226

Full paper : From Pubmed Central site

These are some points of note from the paper :

" human FMO3 is essentially nondetectable in fetal liver, but is observed in most individuals by 1 to 2 years of age...

...Ten- to twenty-fold differences in interindividual FMO expression have been reported that may contribute to an individual’s susceptibility to toxicants and/or response to drugs (Overby et al., 1997; Yeung et al., 2000; Koukouritaki et al., 2002)...

...Thirty genetic variants in human FMO3 coding sequences have been characterized. Thirteen of these are single nucleotide changes that result in loss of function and represent rare alleles causative for trimethylaminuria (TMAU) or "fish-odor syndrome" (for review, see Cashman, 2004). In addition, a homozygous deletion of exons 1 and 2 was reported as causative in an Australian of Greek ancestry with TMAU (Forrest et al., 2001). However, the substantial differences in FMO3 expression observed within or among different populations (Overby et al., 1997; Yeung et al., 2000; Koukouritaki et al., 2002) cannot be attributed to such rare alleles. Rather, common variants encoding an altered, but functional FMO3 must contribute. Three of the 30 known human FMO3 genetic variants (E158K, V257M, and E308G) are common (i.e., allelic frequencies >1%), two of which are associated with reduced FMO3 activity (for review Cashman, 2004). However, considering the percent loss of activity and their frequency, these variants would not fully explain observed interindividual differences in FMO3 expression...

...Hispanic-Americans of Mexican descent, African-Americans, and non-Latino Whites of northern European descent. Haplotype 2 (g.-2650C>G, g.-2543T>A, and g.-2177G>C), exhibited an 8-fold increase in FMO3 promoter activity [probably a good thing], and, combined with its estimated frequency, would be expected to have a significant impact on FMO3 expression and FMO3-dependent xenobiotic metabolism within all three populations. Although haplotype 2's frequency differed among these groups (Table 7), assuming conformity to the Hardy-Weinberg equilibrium, it is anticipated 49.4%, 20.6% and 12.2% of Hispanic-Americans of Mexican descent, African-Americans, and non-Latino Whites of northern European descent, respectively, would possess at least one of the haplotype 2 alleles...

...In contrast to the increased promoter activity observed with haplotype 2, a nearly complete loss of promoter function was observed with haplotypes 8 and 15. Interestingly, haplotypes 8 and 15 were only estimated as common in the Non-Latino White-American and African-American study populations, respectively. Again assuming conformity to the Hardy-Weinberg equilibrium, at least one haplotype 15 allele would be observed in 3.0% of African-Americans while the haplotype 8 allele would be observed in 7.3% of Non-Latino White-Americans...

...The frequencies of these functionally significant alleles in the three population groups strongly suggests that genetic diversity within the FMO3 promoter contributes substantially to observed interindividual differences in FMO3 expression levels. Further, the apparent absence of the loss of function haplotypes 8 and 15 in the Hispanic-American study population combined with the relative abundance in this group of the gain of function haplotype 2 allele would be consistent with FMO3 mean expression being higher in Hispanic-Americans. ..

...Both haplotype 8 and haplotype 15 share a common SNP, i.e., g.-2106G>A, suggesting that this transition may be responsible for the dramatic loss of promoter activity...

...The magnitude of loss of function for haplotypes 8 and 15, suggests both these alleles might contribute to the incidence of trimethylaminuria in the Non-Latino White-American and African-American populations, respectively...

...Studies on individuals heterozygous for structural FMO3 null variants suggest that a 50% loss of metabolic capacity to N-oxidize trimethylamine does not result in an overt trimethylaminuria phenotype, but only renders such individuals susceptible to a trimethylamine challenge (Zschocke et al., 1999). Thus, assuming conformity to the Hardy-Weinberg Equilibrium, one would predict that only individuals homozygous for either haplotype 8 at a frequency of 0.1% in the Non-Latino White-American population or haplotype 15 at a frequency less than 0.1% in the African-American population would present with symptoms for this disorder. In contrast, a 50% loss of metabolic activity in the more frequent heterozygotes may significantly impact FMO3-dependent drug metabolism...

...In summary, a total of 40 FMO3 SNPs have been identified, 27 of which are novel...

... These observations suggest that genetic variation within FMO3 regulatory sequences will contribute to differences in FMO3 metabolic capacity both within and among different populations. Further, these differences may well contribute to differential susceptibility to environmental toxicants and adverse drug reactions both on an individual and population basis. "

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