Liver detox gene:CYP2D6

CYP2D6 is one of the most important enzymes associated with detoxification. 25% of clinical drug clearance is carried out by this enzyme, which includes antitumor drugs and antipsychotic drugs. This enzyme is also responsible for the metabolism of serotonin and dopamine and it also constitutes 40% of hepatic human phase I metabolism.

As humans, we are exposed to a lot of toxins, from the natural plant-based toxins to man-made toxins, to the pollutants discharged by chemical factories to chemicals present in skin creams among others. Our body, however, has the ability to remove certain toxic waste from it. The CYP2D6 enzymes coded by the CYP2D6 genes play an important role in liver detox.

 

Evolutionary and molecular aspects of CYP2D6

CYP2D6 belongs to the cytochrome P450 family of genes which originated from a prokaryotic ancestral gene. The CYP family of genes were instrumental in protecting the prokaryotes form oxygen toxicity. These genes constantly expanded and about 1.5 billion years ago, they expanded to include genes that were endogenous compound metabolising. The last expansion of the CYP genes occurred about 400 million years ago.

The CYP family of genes are found to be one of the most  rapidly evolving genes, an imperative characteristic required to protect cells and to avoid injuries when the cells are exposed to toxins.

The CYP2D6 gene is present in chromosome 22q13.1 and contains more than 100 allelic variants. With the advent of farming and modern day practices, humans have restricted the type of food consumed. This has lead to a loss of selection pressure which is required to keep genes active. Therefore, humans have only one functional gene, while other organisms like rat or mouse have multiple.

CYP2D6 metabolizer status:

Evolution of human CYP2D locus has resulted in the following types of alleles

  • alleles that are fully functional
  • alleles with reduced function
  • null alleles.

The metabolic activity of CYP2D6 depends on the highest functioning allele

CYP2D6 metabolizer statusAllelesGeographic distribution
Ultrarapid Metabolizers (UMs)2 fully functional alleles16% of Ethiopians, 3–5% of Caucasians, 2% of Swedish Caucasians. UMs are present in Oceania and North Africa.
Extensive Metabolizers (EM)One fully functional and one reduced function allele70–80% of Caucasians
Intermediate Metabolizers (IM)2 reduced function alleles or one reduced function and one non functional allele10–17% of Caucasians. IMs are mainly in Asia
Poor Metabolizers (PM)2 non functional alleles19% of African Americans, 5–10% of Caucasians,1% Chinese population and 0.6% of South Indian population.
PMs are found mainly in Europe


Genetic Variants of CYP2D6 – How is it important?


“Identifying the CYP2D6 variant carried can help in finding out which medications will work for you or which toxins you are hypersensitive to.”

The detox genes we carry work at different efficiencies and finding out about those helps us in understanding the metabolism and dosage of various drugs. A lack of CYP2D6 enzyme is associated with lowered drug effectiveness among drugs that require activation by CYP2D6

Use your 23andme raw data or your Ancestry DNA raw data to check for rs1135840 (CYP2D6 s486t )

This is one of the important and well known SNP of CYP2D6- CYP2D6 s486t

GenotypePhenotype
CCTwo non functioning alleles
CTOne non functioning allele
TTNormal

Use your 23andme raw data or your Ancestry DNA raw data to check for rs1065852

GenotypePhenotype
AATwo non functioning alleles
AGOne non functioning allele
GGNormal

Use your 23andme raw data or your Ancestry DNA raw data to check for rs5080367

GenotypePhenotype
GGTwo non functioning alleles
TGOne non functioning allele
TTNormal

Apart from these SNPs that are reported in the 23andme reports, there are other important CYP2D6 polymorphisms which contribute to determining CYP2D6 activity. Authority sites like Pharm GKB list out the significant polymorphisms, all of which are included in the Xcode Life science’s PGX report. Upload your 23andme raw data or your ancestry DNA raw data into Xcode Life science’s dashboard to get your comprehensive report.

For the entire list of CYP2D6 inducers and CYP2D6 inhibitors, check out CYP2D6 in wikipedia.

As the liver is the major source of the CYP2D6 enzymes, ensuring a healthy liver is important.

What is the need for a liver detox?

Every individual should focus on liver detox, especially with the amount of processed foods that are consumed and the amount of synthetic chemicals that enter our water and food supply through industrial, agricultural and other activities. While people may look good on the outside, their internal organs may be stressed due to non clearance of toxins.


The liver is responsible for many essential functions like

  1. It plays a role in protein, fat and carbohydrate metabolism
  2. Produces bile which is essential for breaking down fats
  3. Associated with storage of fat soluble vitamins
  4. Production of cholesterol: According to Harvard health reports, the liver produces 1000 mg of cholesterol which is required for the production of vitamin D, bile and hormones
  5. Protein synthesis: According to a study by Brown University, the liver is responsible for the synthesis of certain proteins that are required for the clotting of blood and for transporting nutrients.
  6. The liver plays a role in maintaining blood sugar
  7. Detoxification: The liver contains numerous enzymes that play a role in detoxification. A healthy liver can transform a potentially harmful substance into harmless products to be excreted.

 

The detoxification potential of a liver is very important and makes it important to focus on liver detox to keep it healthy.

How to detox liver naturally- 6 tips for detoxification

                                           

  1. Vegetable juice: Vegetables are a good source of nutrients and fibre which help in detoxifying the liver. Since it is difficult to consume a lot of salad, juicing vegetables like cabbage, brussels sprouts, beetroot, beans, carrots and cucumber may be the next best thing to do. Adding a dash of lime or mint could improve flavour.
  2. Bust the visceral fat: A study published in nature showed that the presence of excess of visceral fat leads to a protein called TRIP-Br2 initiating an inflammatory response. Regular exercise will help in reducing visceral fat.
  3. Intermittent fasting: Intermittent fasting will help in lowering fat content and is also found to increase stem cells which are needed to regenerate organ tissue.
  4. Avoid processed foods: Processed foods are high in saturated fat, sugar and salt, all of which get the liver to work harder. This can affect liver health over time. Therefore, the first step would be to avoid such foods.
  5. Increase intake of Vitamin C : Vitamin C plays an important role in reducing inflammatory markers. Detox water, which is nothing but lime water, consumed regularly could up your levels.
  6. Broccoli sprout extract: A study by researchers from The University of Tokyo showed that consumption of broccoli sprout extract protected the liver from xenobiotic substances by upregulating certain detox genes and by glutathione synthesis.

 

Genetic testing for medication effectiveness- CYP2D6

There is an intricate drug-gene interaction which makes genetic testing for medication effectiveness imperative.

DNA testing for drug effectiveness can be used for the following

  • The response of the individual to the drug
  • The dose necessary for a favourable response
  • The extent of side effects that may be caused due to the gene

 

Pharmacogenomics is a growing industry with many physicians utilising DNA testing for drug effectiveness. The significance of this method of testing was understood by the former President of the United States, Mr. Barack Obama, who felt that pharmacogenomics could make US healthier. He had wanted to dedicate $215 million towards precision medicine in his budget, signalling the growing interest in the field.

 

CYP2D6 gene polymorphisms are included in the Xcode PGX reports and should be interpreted only by a medical practitioner to identify the right drug and the right dose for each individual.  

References:

  1. https://www.nature.com/articles/ncomms11378
  2. https://www.ncbi.nlm.nih.gov/pubmed/29727683

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