Arsenic detoxification and your genes

While arsenic may bring to mind Agatha Christie’s mysteries, it turns out that it is a fairly common toxicant in well water. People around the world are exposed to it on a daily basis.

This article covers the pathways the body uses to get rid of arsenic, and it includes information on genetic variants that may impair the detoxification of arsenic.

Arsenic, detoxification pathways, and genetics:

Let’s start with a bit of background science: what exactly is arsenic and how do we get rid of it?

Arsenic is a naturally occurring semi-metal metalloid and usually found as a compound with other minerals. Arsenic exposure occurs via well water, in certain foods, and through breathing (industrial pollution).

Your body has built-in pathways for removing arsenic. It is a naturally occurring toxin, and animals have detoxification pathways for getting rid of it – up to a point…Arsenic is, of course, deadly at certain levels. Your genes impact how well your body gets rid of arsenic.

In the US, about 7% of water wells contain arsenic at levels of 10 µg/L. The EPA lowered the target level of arsenic from 50 µg/L (50 ppb) to 10 µg/L (10 ppb) in 2006.[ref]

If you live in the US, here is a USGS map showing counties that have a higher exposure to arsenic in the well water.

Arsenic in well water – county map from the USGS.

Arsenic can also be found in foods grown in contaminated soil or water. For example, depending on where rice is grown affects its varying amounts of arsenic. Organic brown rice grown in Australia contains about the maximum WHO recommended daily limit of arsenic. This compares with rice from India, which contained about a quarter of that amount.[ref]

We are all likely exposed to small amounts of arsenic all the time, and the body has built-in ways of getting rid of it.

How does your body get rid of arsenic?

Arsenic is eliminated from the body in a couple of steps:

  1. metabolized (broken down) into methylarsonic acid and dimethylarsinic acid
  2. then excreted in the urine

Getting a little more in-depth: The process of metabolizing arsenic, so that it can then be excreted in the urine, involves both methylation and redox reactions. Methylation refers to adding a methyl (CH3) group to the molecule. And the redox reaction involves glutathione as the reducing agent. The key is that once this detoxification process starts, it all needs to continue on to the point of excretion. This is because some of the intermediates that are formed are more toxic.[ref]

The enzyme called Arsenite methyltransferase (AS3MT) helps add the methyl group to arsenic. It uses a methyl group, so it is thus dependent on the body having sufficient methyl groups available.

For the redox reactions that take place during arsenic metabolism, the cells use up glutathione. Thus, adequate glutathione is also necessary here.

How Does Arsenic Cause problems in the body?

Arsenic as poison has a long history. Arsenic trioxide was called “succession” or “inheritance powder”, and historically used in Italy and France to poison several leaders. The Borgias family in Italy is famous for using a little arsenic in the wine to gain wealth and power.[ref] In the Victorian era, a pale complexion was all the rage. Women would mix vinegar, chalk, and arsenic trioxide together and eat it to become pale (poisoning themselves slightly, in the name of beauty).

Arsenic poisoning – high doses:

A high dose of arsenic can cause death. This is because arsenic interrupts your cells’ ability to create ATP (cellular energy). Arsenic in different forms can affect either glycolysis (turning glucose into energy) or Kreb’s cycle (producing ATP/energy in the mitochondria). As you can imagine, reducing the production of ATP isn’t a great idea. If you reduce ATP enough, cell death occurs.

Skin lesions and cancer:

Chronic exposure to arsenic at higher levels (>100 μg/L in drinking water) increases the risk of skin lesions[ref] and basal cell carcinoma, a type of skin cancer.[ref]

At higher levels, arsenic increases the risk of skin lesions or cancer for everyone. But some people may be at an increased risk with only moderate levels of arsenic exposure. Genetic variants associated with less efficient arsenic methylation have links to a slight increase in the risk of basal cell carcinoma (skin cancer).[ref]

You may be wondering if showering or bathing in water that contains arsenic causes skin cancer. That doesn’t seem to be the case. Arsenic is not well absorbed transdermally; instead, the consumed (food, water) arsenic concentrates in skin, hair, and nails.[ref]

Chronic low exposure to arsenic uses up glutathione

While lower amounts of arsenic in drinking water (<50 μg/L) may not cause death or cancer, there can be long-term consequences.

Constantly detoxifying arsenic causes a lot of glutathione to be consumed by the body. Glutathione is an antioxidant that the body produces to combat oxidative stress in cells and to detoxify certain substances -including arsenic.[ref]

When arsenic goes through the process of being methylated so that it can eventually be excreted in the urine, the intermediary compounds produced are actually more toxic than the original inorganic arsenic. So if the cells don’t have enough glutathione or methyl groups available to complete the detoxification and then excretion, the more toxic metabolites can hang out in the body too long. This is one way that arsenic increases the risk of cancer.[ref]

Arsenic can also increase oxidative stress in the cells in several ways, such as through impacting mitochondrial energy production. Nrf2 is one way that cells can combat oxidative stress. Indeed, research shows that arsenic exposure upregulates the Nrf2 pathway, and Nrf2 acts to protect the cells against arsenic.[ref]

Genetic variants that impact arsenic detoxification:

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AS3MT gene:  The AS3MT (Arsenite methyltransferase) enzyme is an S-adenosylmethionine (SAMe) dependent enzyme that adds a methyl group in the conversion of arsenic for excretion. Genetic variants in AS3MT can increase or decrease the enzyme function.

Check your genetic data for rs11191439 M287T (23andMe v5, AncestryDNA):

  • C/C: increased risk of skin lesions with arsenic exposure[ref]
  • C/T: increased risk of skin lesions with arsenic exposure;
  • T/T: typical

Members: Your genotype for rs11191439 is .

Check your genetic data for rs3740393 (23andMe v4, AncestryDNA):

  • C/C: higher arsenic metabolites in the urine (more excretion)[ref]
  • C/G: typical
  • G/G: typical

Members: Your genotype for rs3740393 is .

GSTO1 gene: encodes a glutathione-S-transferase enzyme, which is essential in getting rid of arsenic.[ref] Additionally, it plays a role in neutralizing oxidative stress.[ref]

Check your genetic data for rs4925 (23andMe v5; AncestryDNA):

  • C/C: typical (most common);
  • A/C:  increased skin lesions in arsenic poisoning[ref]; decreased excretion of arsenic in urine[ref]
  • A/A:  increased skin lesions in arsenic poisoning; decreased excretion of arsenic in urine[ref]

Members: Your genotype for rs4925 is .

MTHFR gene: the MTHFR enzyme is important in folate metabolism and supplies methyl groups for the methylation cycle. Animal studies show that lower levels of MTHFR are linked to problems with arsenic detoxification.[ref]

Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: typical *
  • A/G: one copy of MTHFR C677T allele (heterozygous), decreased by about 40%[ref]; decreased arsenic detoxification and increased skin lesions with arsenic exposure
  • A/A: two copies of MTHFR C677T (homozygous), decreased by 70 – 80%; decreased arsenic detoxification and increased skin lesions with exposure[ref][ref]

Members: Your genotype for rs1801133 is .



Test your well water: The biggest source of arsenic exposure for most people is drinking well water that has high levels. Water testing is relatively inexpensive and will let you know your exposure. If your well water comes back higher in arsenic, consider remediating with a reverse osmosis filter system.

Folate: Get your methylation cycle on track. The methylation cycle is at the heart of many processes in the body, including arsenic detoxification. If you carry the MTHFR C677T variant, it is essential to get enough folate daily. Higher levels of folate intake reduce the risk of arsenic toxicity.[ref]

Foods high in folate include dark leafy green vegetables, lentils, and beef liver. Additionally, methyl folate supplements are available. The recommended daily intake of folate is 400 ug. (Check your COMT variants before supplementing with high doses of methyl supplements).

Lifestyle factors: Smoking and drinking both decrease your ability to get rid of arsenic.[ref]

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Related Articles and Genes:

Detoxification: Phase I and Phase II metabolism
Learn how the different genetic variants in the phase I and phase II detoxification genes impact the way that you react to medications and break down different toxins.

Nrf2 Pathway: Increasing the body’s ability to get rid of toxins
The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. This is a fundamental pathway that is important in how well your body functions. Your genetic variants impact how well this pathway functions.

MTHFR – Beyond C677T and A1298C
The folate cycle interacts with the methylation cycle, supplying the body’s need for methyl groups. But C677T and A1298C do not give the whole picture for the MTHFR gene. There are additional variants that also impact the functionality of the enzyme.

GSTs: glutathione-S-transferase enzymes for detoxifying environmental toxins
Your body has fascinating ways of breaking down and eliminating toxicants, medications, and even hormones made in the body. The glutathione S-transferase genes code for enzymes involved in the removal of a variety of carcinogens and environmental toxins.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.