This new paper looks at variants in the FMO1 enzyme. For context, a quote about the function of human FMO1 can be read in this 2005 paper, with this quote from it :
In humans, FMO1 is the major FMO in fetal liver and adult kidney and intestine. The human is a very interesting species with respect to developmental regulation of FMO1 and FMO3. FMO1, the major FMO in liver of most adult mammals, is expressed at relatively high concentrations in human fetal liver, but shortly after birth, expression is reduced to almost zero; the signal for termination of expression is related to the parturition and not to gestational age (Hines & McCarver, 2002; Hines et al., 2003). FMO1 may play an important role in extrahepatic drug metabolism in humans as well as in the liver of the fetus exposed to numerous potential xenobiotic substrates in utero. Currently, there are ~20 allelic variants of human FMO1 described by Furnes et al. (2003) and Hines et al. (2003) and the GeneSNPs database. The enzymatic activity of some of the FMO1 variants are given in Table 4. Based on the work of Hines et al. (2003), some of these allelic variants are probably rare alleles (H97Q, I303V, I303T, R502X) and may not contribute significantly to interindividual differences in FMO1 expression. On the other hand, a much more common variant (FMO1*6) caused by a C→A transversion in the upstream promoter region (−9,536), may impact FMO1 expression as it renders a Yin Yang basal promoter incapable of binding YY1 (Hines et al., 2003). The allelic frequency ofFMO1*6 is 13, 11, and 30% in African–Americans, northern European–Americans, and Hispanic–Americans, respectively (Hines et al., 2003).
2005 FMO paper : Krueger & Williams
NEW FMO1 PAPER : NICOTINE DEPENDENCE
Nowadays, geneticists are often looking at enzymes for possible health related issues. Whether it is wiser for readers to wait until a trend occurs in research papers is up to each reader. In this paper, they did seem to choose the 3 main groups of families of enzymes likely to handle nicotine detoxification. Their conclusion is that out of these groups of enxymes, common FMO1 polymorphisms (variants) seem to be linked with nicotine dependence. It is of interest that Dr Cashman has previously found that a part of nicotine will be detoxified by FMO3.
NEW PAPER : Common polymorphisms in FMO1 are associated with nicotine dependence
Abstract
BACKGROUND:
Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world. A better understanding of the etiology of nicotine addiction may help to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking.METHODS:
To identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes, flavin monooxygenases (FMOs), and UDP-glucuronosyl transferases.RESULTS:
Several polymorphisms in FMO1 showed association in a discovery sample, and were tested in an independent replication sample. One polymorphism, rs10912765, showed an association that remained significant after Bonferroni correction (nominal P=0.0067, corrected P=0.0134). Several additional polymorphisms in linkage disequilibrium with this single nucleotide polymorphism also showed association. Subsequent in-vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue.CONCLUSION:
These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology.
FMO : wikipedia
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