Dr. Damien Downing's Column
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Thursday, January 13th, 2011:
Genomics and Detox Capacity
by Damien Downing MD
Various media have recently declared that detox treatments are a waste of time, because all you need is a liver and kidney. Well, yes and no. Yes, it’s clear that there are all sorts of products sold over-the-counter that are worthless, and that most detox diets amount simply to stopping taking toxins in for a while, not to actually removing them. But no, we do all have liver and kidneys, but they are not all the same because of variations (“polymorphisms”) in the genes, and thus in the enzymes. The detox system is amazing, but not perfect. Nowadays we are all exposed to far more toxins than the system developed to handle, and it is possible to overload our detox capacity - particularly if we have genetic polymorphisms.
A very quick introduction to genomics
Remember that we each have, in every cell, 2 copies of each of the 23,000+ genes that determine our heredity, one from each parent. The old genetics was about being able to say, for example, “Your child has a 25% chance of having Down’s Syndrome”; the new genomics enables us to say “Untreated, you have 3 times the population-average risk of developing Alzheimer’s, but there are things you can do about it”. We can do this because since the Human Genome Project we have been learning to identify the SNiPs ( Single Nucleotide Polymorphisms) on our genes. These small changes in our DNA can have large effects on our chemistry.
You can have both copies of the gene normal, both copies abnormal (with the SNiP) or one of each. Having both the same is termed homozygous, having one of each heterozygous.
For instance, if you receive a report that you have a variation/polymorphism called MTHFR (C677T) this means that in the MTHFR gene (which codes for Methyl-Tetra-Hydro-Folate Reductase, the key enzyme that activates folic acid), at position 677 counting from the start of the chromosome, the base Cytosine is replaced with Thymine. That one-base alteration will reduce the activity of the enzyme that is produced, especially if you are homozygous for the change. In real life that change is associated with an increased risk of autism, and of heart disease because of a molecule called homocysteine.
A quick guide to hepatic detox
Detoxification is one of the most-studied areas in genomics; while the whole subject is complicated, with at least 30 main enzymes (not counting the variations possible in each of them), sometimes a clear pattern emerges from the report.The detox process splits into two successive phases.
Phase 1 Detox
All the Phase 1 enzymes are members of a large family called Cytochrome P450 (which is why the genes for these enzymes are all called CYP-something, and we now tend to use that abbreviation for the enzyme as well as for the gene).
Other CYP enzymes activate and inactivate hormones, vitamins and other naturally-occurring molecules, not to mention drugs and pollutants, but what almost all of them do is to oxidize - to add an oxygen atom to a molecule. In fact we used to call them the Mixed Function Oxidases. This oxidation makes the molecule more reactive, and in detox that means that it will react better in Phase 2. But it also means that until it is inactivated it is a free oxidising radical (the molecules against damage from which we take antioxidants).
There is a lot of data online about the CYP enzymes now, and for each enzyme the database typically gives several lists of chemicals:
Substrates; the chemicals that the enzyme processes, oxidises and (usually) activates
Inducers; chemicals that switch the gene on to produce the enzyme
Inhibitors; chemicals that switch the gene off
One important enzyme here is CYP1A2, which processes the following substrates;
- some common drugs such as antidepressants
- naturally-occurring hormones such as oestrogens
- caffeine (nearly all of it)
- heterocyclic amines (present in burnt or heavily-cooked meat)
Inducers of the gene include;
- burnt meat
- tobacco smoke
- cruciferous vegetables (broccoli, sprouts, cauliflower)
- oral contraceptives (which is also a substrate)
Phase 2 Detox
The Phase 2 enzymes combine the activated molecule to something that inactivates it, and it stays that way while it is excreted out of the body. The main such reactions are called;
- glutathione conjugation (binding to glutathione)
- sulphation (binding to sulphate)
- glucuronidation (for more about which see my item on Gilbert’s Syndrome)
- peptide conjugation (binding to either glycine or taurine)
Glutathione conjugation is the biggest of these reactions, amounting to maybe 50-60% of all Phase 2 activity; the enzymes involved (about a dozen sub-types) are all called glutathione-S-transferases, and the genes all GST-something; GSTM1 codes for the most important enzyme in the liver, while GSTP1 and GSTT1 are more important elsewhere.
Interestingly, GST enzymes are also induced by cruciferous vegetables.
What can go wrong?
There is a common polymorphism of the CYP1A2 Phase 1 gene that makes it much more inducible - perhaps 100 times more. If you have that polymorphism, particularly if you are homozygous for it, then when you are exposed to a substrate, such as burnt meat products (aka barbecues), and to an inducer, your enzyme can process, activate, a lot more substrate than the next person. In Europe about 50% of us have at least one variant copy of the gene.
The commonest polymorphism of the GSTM1 Phase 2 gene, on the other hand, makes it completely inactive, or “null”. if you are homozygous for that you have lost a big part, about 1/3, of your total detox capacity. And about 50% of us have at least one copy of that gene, too (in Europe, again). That means that around 5% of Europeans are homozygous for both polymorphisms.
It is obvious what will happen if you have both these changes in your genes; in Phase 1 you will in certain circumstances produce a lot more free radicals than your Phase 2 can dispose of. And because the route of excretion of these toxins from the liver is through the bile and into the gut contents, it is likely that this can trigger or worsen all sorts of disorders of digestion and bowel function. Having the two polymorphisms together has already been linked to an increased risk of bowel cancer.
Now consider the inducers, particularly the cruciferous vegetables which, via a molecule called sulphoraphane, induce both CYP1A2 and GSTM1. Normally this is a good thing, helping you to get rid of more toxins. But if you have these changes in both genes, the cruciferi can activate the Phase 1 enzyme even more, but the Phase 2 enzyme not at all, so making the build-up of free radicals even worse.
What can be done?
This “double-whammy” effect (I’m sorry, there isn’t a scientific term for it that I know of) is a striking example of what can go wrong with our genes. There are many other combinations of polymorphisms that have been linked to all sorts of diseases - particularly cancer, which understandably has had the most research attention, but also chemical sensitivities, heart disease, Alzheimer’s - the list goes on. But with a genomic profile we can help you to work out the best way of mimimising your risk, whatever your genomic inheritance. Because your genes are only the beginning of the story; next comes epigenetics, the study of how genes are switched on and off - and often the answer to that is nutritional. Vitamin D, for instance, is so far known to influence the expression (switching on) of at least 1,000 genes.
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