Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

LOX, leukotriene production and epigenetics

with 2 comments

DNA methylation as an epigenetic regulator of neural 5-lipoxygenase expression: evidence in human NT2 and NT2-N cells Epigenetic phenomena are defined as changes in the genetic material that alter gene expression in a somatically heritable manner but do not change the DNA sequence […]

Recently, epigenetic mechanisms have been implicated in the regulation of central nervous system (CNS) gene expression and CNS function […]

5-Lipoxygenase (EC, 5-LOX) is the key enzyme in the metabolism of arachidonic acid into inflammatory leukotrienes (Funk 2001). However, the evidence for 5-LOX gene expression in the CNS (Lammers et al. 1996) suggests a role for the 5-LOX pathway in CNS function (Manev and Uz 2002a, 2003). The increased expression of brain 5-LOX has been associated with neurodegeneration (Whitney et al. 2001; Tomimoto et al. 2002), aging (Uz et al. 1998; Qu et al. 2000), and the pathology of brain tumors (Boado et al. 1992; Golubic et al. 2003). […]

It has been demonstrated that the cell line-specific expression of 5-LOX may be controlled by epigenetic mechanisms that involve DNA methylation (Uhl et al. 2002). These mechanisms could also participate in cell cycle-dependent and drug-induced regulation of 5-LOX expression; for example, differentiation-induced down-regulation (Uz et al. 2001) and drug-induced up-regulation (Manev and Uz 2002b). However, there is no direct evidence that the DNA methylation status of the 5-LOX gene changes under these conditions. Moreover, even the normal state of methylation of the gene promoter in neural cells is unknown. To address these questions, we investigated the relationship between 5-LOX expression and the methylation state of the 5-LOX core promoter in an in vitro model of human neurons. […]

In conclusion, the demethylating effects of VPA on the 5-LOX promoter and the stimulatory action of VPA on 5-LOX expression in NT2-N neurons along with similar actions of AdC in proliferating NT2 cells indicate that neural 5-LOX expression can be epigenetically regulated. We propose that in the epigenetic regulation of neural gene expression, CpWpG methylation may serve as a supplementary suppressive mechanism complementary to CpG methylation, and that both mechanisms are susceptible to pharmacological modulations. We also found that DNA methylation state is modifiable in neurons and we propose that neurons may have a special methylating/demethylating machinery different from other tissues. DNA methylation as an epigenetic regulator of neural 5-lipoxygenase expression: evidence in human NT2 and NT2-N cells Abstract, PDF

In English, poor DNA methylation leads to the heightened expression of LOX, and therefore increased leukotriene production in the central nervous system. This heightened expression can be passed on epigenetically to offspring, but also appears to be modifiable throughout one’s lifespan depending on how well an individual is able to methylate their own DNA.

The list of problems associated with increased leukotrienes is interesting and scary: neurodegeneration, aging, and brain tumours. ‘VPA’ stands for valproic acid, an inhibitor of DNA methylation. Neurodegeneration has long been observed in epilepsy, but it has always been blamed on the epilepsy itself. I wonder whether it has more to do with the negative impact of valproate?

Back to leukotrienes. We have known for some time that:

Pathophysiologically speaking, symptoms of salicylate intolerance can be explained by an overproduction of leukotriene metabolites, since salicylate intolerant patients who have come in contact with salicylate containing substances show a marked inhibition of cyclooxygenase (COX-1), which is continuously expressed in the body (Fig. 1) (2, 8). On one side this leads to a diminished production of typical cyclooxygenase products (e.g. tissue-protective prostaglandin derivatives, prostacyclin, thromboxan), while on the other it accelerates the metabolization of arachidonic acid towards leukotriene A4 (9). Significance of salicylate intolerance in diseases of the lower gastrointestinal tract Abstract, PDF

I’ve been somewhat puzzled by the leukotriene connection and how this fits with the methylation/detoxification information we have about food chemical intolerance – it’s an annoying but significant snag, like trying to fit an explanation for gravity into quantum physics.

Some have theorised that LOX/COX polymorphisms must be involved, but I was never fully convinced that this was the main factor, and the inflammation aspect seems so fully integrated into conditions like autism and fibromyalgia.

What this gives us is the possible mechanism that brings things together: if you are unable to methylate your DNA properly, you will overexpress LOX and therefore produce excess leukotrienes.


Written by alienrobotgirl

2 September, 2007 at 10:22 am

Posted in The Science of FCI

2 Responses

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  1. WOW!I loved your comments on inhibition of DNA methylation as being possibly causal in various neurodegenerative disorders!I have read some papers in support of this assertion.Epigenetic inheritance is fascinating!Is the current emphasis in research on genetic inheritance alone somewhat misplaced?How does the environment we inhabit influence gene expression,especially amongst young children,who are much more receptible and in much closer contact?


    22 December, 2007 at 7:19 pm

  2. Hi SteveI agree epigenetics is fascinating! I think there are significant amounts of research going on, it’s just something that’s not in the public consciousness. However, I think most of the answers to food chemical intolerance lie in unfortunate combinations of regular old-fashioned single nucleotide polymorphisms.

    Alien Robot Girl

    30 January, 2008 at 1:34 pm

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