Crohn's Disease; Link to POPs and Polymorphisms in Detox Enzymes
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From: jay on 17 Sep 2008 20:11 Many Persistent Organic Pollutants (POPs) are detoxified by cell's CYP1 enzymes into secondary and sometimes more toxic metabolites. And microsomal epoxide hydrolase (mEH) converts the secondary metabolites into water soluble metabolites for execretion by kidney. According to below abstract, those with CD had significantly higher incidence of a polymorphisms in mEHs. Genetic polymorphisms in biotransformation enzymes in Crohn's disease: association with microsomal epoxide hydrolase. BACKGROUND: Mucosal biotransformation enzymes can modify toxic compounds in the gut. As chemical or oxidative stress may be involved in the aetiology of Crohn's disease, genes encoding for enzymes involved in the prevention of such stress may be candidates for genetic susceptibility to Crohn's disease. Aim: To assess the association of Crohn's disease with genetic polymorphisms in cytochrome P450 1A1, glutathione S-transferases mu-1, pi-1, and theta-1, and epoxide hydrolase. METHODS: ... analysis was used to compare frequencies of polymorphisms between 151 patients with Crohn's disease and 149 healthy controls. RESULTS: In patients, a genetic polymorphism in exon 3 of the microsomal epoxide hydrolase gene was distributed significantly different compared with controls. All other polymorphisms tested were equally distributed between patients and controls. CONCLUSIONS: Microsomal epoxide hydrolase may play a role in the pathophysiology of Crohn's disease. Furthermore, the epoxide hydrolase gene is located on chromosome 1q, close to a region previously linked to Crohn's disease. PMID: 12631667
From: Kofi on 18 Sep 2008 13:44
I don't know if you paid any attention to my article on CMV and HDACs but there are several different gene products involved with butyrate metabolism that depend on proper HDAC inhibition - the mu opioid receptor (and eventually cannabinoid signaling and B-cell proliferation), IDO, FoxP3, metallothionein, autophagy and innate antimicrobial defensins/cathelicidins. Defects in these pathways are associated with Crohn's/IBD/colitis. CMV can cause colitis and HDAC inhibitors like butyrate can reactivate the virus so the body may well be adopting a "butyrate resistance" or "carnitine resistance" strategy to keep the virus from replicating and this adaptation to fight the virus then causes a case of colitis. Once down this road, you've lost metallothionein expression and toxins are going to accumulate. We also know metals can reawaken herpesviruses and if my hypothesis is true then these viruses can, in turn, lead to metals accumulation by shutting down metallothionein. You'd have to treat both the virus and the toxin accumulation if you want to be in a position to restore the gut's proper detoxification chain. But that's just what's happening in a normal person with a CMV infection. If you have underactive detoxification allelles then you're going to be predisposed to an IBD to begin with. Have you looked at the effect of HDAC inhibition on expression of any of the mEHs? P.S., the 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. |