Crohn's Disease; Link to POPs and Polymorphisms in Detox Enzymes
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From: jay on 17 Sep 2008 22:31 > ... microsomal epoxide hydrolase (mEH) converts the > secondary metabolites into water soluble metabolites > for execretion by kidney... Epoxide hydrolases: biochemistry and molecular biology. Epoxides are organic three-membered oxygen compounds that arise from oxidative metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygenase system. The resultant epoxides are typically unstable in aqueous environments and chemically reactive. In the case of xenobiotics and certain endogenous substances, epoxide intermediates have been implicated as ultimate mutagenic and carcinogenic initiators. Therefore, it is of vital importance for the biological organism to regulate levels of these reactive species. The epoxide hydrolases belong to a sub-category of a broad group of hydrolytic enzymes that include ... PMID: 11154734
From: jay on 18 Sep 2008 22:10 > Have you looked at the effect of HDAC inhibition on expression > of any of the mEHs? Didn't find an article relating HDAC to mEH, but I'll keep looking. > ... study you cite only shows *one* polymorphism > in mEH (in exon 3) is related to Crohns. > It's unclear if this is a loss- or gain-of-function variant. I think it is a variation (rather than gain or loss) of the enzyme. The variation results in more toxic metabolites under some conditions (ie detox of certain pollutants and estrogens) > .. article on CMV and HDACs > but there are several different gene products involved with butyrate > metabolism that depend on proper HDAC inhibition ... > Defects in these pathways are associated with Crohn's/IBD/colitis... I'll have to read your prior posts on above topics. Would the CMVHDAC hypothesis relate to #1 and #4 below? 1) Shift to industrialization 2) Genetics 3) Smoking & appendectomy 4) Contraceptives (estrogens) [Changes in the epidemiology of inflammatory bowel diseases] Significant changes have been observed in the epidemiology of inflammatory bowel diseases (IBD) in the last two decades. Traditionally, the incidence of IBD was higher in the developed, industrialized countries, in contrast, nowadays it became more prevalent in the previously low incidence areas. In particular, the incidence of ulcerative colitis (UC) is similar to that observed in North America and Western Europe, while the incidence of Crohn's disease (CD) in developing countries is still low, suggesting that the environmental factors may act faster or differently in UC than in CD. In Europe, the North to South gradient disappeared, and also the West to East gradient is diminishing. Smoking and appendectomy may be considered as important environmental factors in both UC and CD, however, with opposite effects. In addition, the use of oral contraceptives is associated to disease susceptibility in both diseases. The role of diet, perinatal events, stress and nonsteroidal anti-inflammatory drugs in the pathogenesis is still controversial. PMID: 17344143 [Epidemiology of inflammatory bowel disease in Asia] Inflammatory bowel disease (IBD) once considered to be a disease only of the Western world is no longer so. Though good epidemiological studies are available from the West, still the information available from Asia is inadequate. This article is a review of the available epidemiological studies from Asia. The incidence / prevalence rates of IBD are still the highest in Europe and North America, though there is convincing evidence of rising trend of IBD in Asian countries; India probably heads the list. There is a need to study the role of various environmental and genetic factors in different countries in Asia. At present, ulcerative colitis predominates but Crohn's disease is expected to manifest more in coming years. PMID: 18431013 [Epidemiology and risk factors of inflammatory bowel diseases] Inflammatory bowel diseases (IBD) are a public health problem in industrialized countries, where 1 in 1000 people are affected Most patients are young adults. The incidence of IBD has increased considerably in western countries since the second world war but is beginning to level off. On the other hand, the incidence is still rising in low-incidence areas such as Eastern Europe, Asia and developing countries. Differences in incidence rates across age, time, and geographic areas suggest that environmental factors are involved in IBD, but only cigarette smoking and appendectomy have consistently been identified as risk factors. An important role of genetic factors in IBD was first suggested by epidemiological studies showing familial aggregation of IBD and by twin studies. In 2001, the first CD susceptibility gene, NOD2/CARD15 on chromosome 16, was characterized. Other susceptibility genes have since been located. Their identification should help to understand the complex interaction between the environment and the intestinal immune system. PMID: 18402167
From: Kofi on 19 Sep 2008 23:59
> > .. article on CMV and HDACs > > but there are several different gene products involved with butyrate > > metabolism that depend on proper HDAC inhibition ... > > Defects in these pathways are associated with Crohn's/IBD/colitis... > > I'll have to read your prior posts on above topics. Would the CMVHDAC > hypothesis relate to #1 and #4 below? I'm not sure what you mean by 'relate.' > 1) Shift to industrialization The influence of industrialization can be explained purely by the extermination of helminths in our G.I. tract (where it's as simple as that is another matter). Helminths appear to upregulate a number of gut protective pathways. Whether helminths offer protection against CMV, I don't know but many commensual organisms help us fight off colonization by more vicious organisms. > 2) Genetics Undoubtedly genetics affects a person's susceptibility to any infection. > 3) Smoking & appendectomy Which one is protective? I'm not familiar with these risks. > 4) Contraceptives (estrogens) Progesterone is directly responsible for the synthesis of antimicrobial compounds like defensins and cathelicidin. Use of the progesterone antagonist RU-486 has been associated with some deadly infections that looks suspiciously like collapse of barrier function. There might be something similar going on with birth control pills. I wouldn't be surprised to find out progesterone had a mildly positive benefit for IBD due to its effects on Th1. |