Phase II Detox – NATs

Once toxins are initially broken down in the body, they must be converted to a water-soluble molecule in order to be excreted.

NATs: N-acetyltransferase

N-acetyltransferase is a phase II detoxification enzyme that helps to metabolize aromatic amines, drugs, cigarette smoke, and carcinogens. Basically, it makes specific toxins more water soluble so that they can be excreted through a process called acetylation.

There are several common genetic variants that can classify a person as a slow, intermediate, or rapid acetylator. The rapid acetylator is considered to be the ancestral type and is the most common type in Asian and African populations; Caucasian people are actually slightly more likely to be intermediate or slow acetylators.[ref]

Historically, N-acetyltransferase was first recognized in the 1950s to play a role in the metabolism of tuberculosis drug. A significant percentage of people were found to be poor acetylators resulting in significant side effects of the tuberculosis drug, isoniazid.


Genetic Variants

NAT1 metabolizes p-aminobenzoic acid (PABA) and p-aminosalicylic acid (PAS).[ref] PABA used to be commonly found in sunscreens, and PAS is used as an antibiotic for tuberculosis.

NAT1 also breaks down components of cigarette smoke and heterocyclic aromatic amines, which forms when meats and seafood are grilled at high temperatures.

Studies link NAT1 the genetic variants to an increased risk of bladder, colon, breast, lung, prostate, and pancreatic cancers. [ref]

Smoking is not good for anyone, but it is even more risky for those with NAT1 slow acetylator variants. NAT1 slow and intermediate acetylators had been shown to have a significantly higher risk for esophageal cancer and lung cancer in smokers.[ref]

Research shows that NAT1 slow acetylators have more DNA adducts formed with heterocyclic aromatic amines (carcinogens from meat being cooked at high temps). DNA adducts are segments of DNA that are bound to a carcinogen and often a precursor for cancerous cells.[ref]  Another study shows that red meat consumption for slow and intermediate acetylators increases the risk of esophageal cancer. [ref]

NAT1 is also involved in folate metabolism and folate may be a co-enzyme for NAT1 hydrolysis of acetyl-Coenzyme A [ref].  Rs15561 -A/A (below) has been associated with cleft lip (especially if the mother smokes) and spina bifida. Note that it is the baby’s genotype, not the mother’s, that is being studied, so this is another really good reason not to smoke. [ref] Both of those conditions are linked to folate metabolism and the methylation cycle.

Check your genetic data for rs4986782 (23andMe v4, v5):

  • A/A: NAT1*14B, slow acetylator [ref]
  • A/G: slow acetylator,
  • G/G: typical

Check your genetic data for rs15561 (23andMe v4):

  • A/A: reduced function [ref]
  • A/C: reduced function
  • C/C: typical

Check your genetic data for rs6586714 (23andMe v4):

  • A/A: lower risk of colon cancer from cooked meat carcinogens (protective) [ref]
  • A/G: lower risk of colon cancer from a cooked meat carcinogens
  • G/G: typical

There are several other SNPs that are not included in 23andMe data so the above SNPs are not the complete picture for NAT1.

NAT2 also catalyzes the acetylation of a couple of types of carcinogens (aromatic and heterocyclic amines) which include tobacco smoke, well-cooked meat, and exhaust fumes. NAT2 is found mainly in the liver, in contrast with NAT1, which is found throughout the body. NAT2 has been studied extensively and is thought to play a role in the risk for several types of cancers.

NAT2 polymorphisms also create rapid, intermediate, and slow acetylators. Slow acetylators don’t clear out toxins as well and are at a somewhat higher risk for bladder, lung, breast, and esophageal cancers. Rapid acetylators can actually make some toxins more reactive and may be at a slightly higher risk for colon cancer.

There is an online tool from the University of Albany to determine your NAT2 phenotype.  http://nat2pred.rit.albany.edu/  You will need to look up your data for six different SNPs.   It asks you to put in your NAT2 alleles for the following:

NAT2 rs1208 – A, has also been found to be involved in increased insulin resistance, although, to me, the effect looked pretty small.  [ref]

NAT2 is also being studied in relation to bacteria which can produce it, and their relationship to drug metabolism.


Lifehacks

If you need another reason not to smoke, being a slow or intermediate acetylator is a really good reason to never pick up a cigarette.

Slow acetylators may want to cut back on fried meats to limit the intake of heterocyclic aromatic amines.

Further reading:

Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.