Phase II Detox – NATs

N-acetyltransferase  is a phase II detoxification enzyme that helps to metabolize aromatic amines, drugs, cigarette smoke and carcinogens.  It is also involved in the folate cycle.  In the 50’s, it was recognized 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.  (Acetylation is the conjugation of a toxin with acetyl-Coenzyme A.)  There are several common polymorphisms that can classify a person as a slow, intermediate or rapid acetylator.  Although the rapid acetylator is considered to be the ancestral type and is most common in Asian and African populations, Caucasian-European people are actually slightly more likely to be intermediate or slow acetylators. [ref]

 

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.  It also breaks down components of cigarette smoke and heterocyclic aromatic amines.

There have been studies linking NAT1 polymorphisms to bladder, colon, breast, lung, prostate, and pancreatic cancers. [ref]

Smoking is even more risky for those with NAT1 polymorphisms.  NAT1 slow and intermediate acetylators had ben shown to have significantly higher risk for esophageal cancer and lung cancer in smokers.  [ref] It has recently been found that NAT1 slow acetylators have more DNA adducts formed with heterocyclic aromatic amines (carcinogens from meat being cooked at high temps). [ref]  Another study also found red meat consumption for slow and intermediate acetylators to be linked to 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 -AA (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 with folate metabolism and the methylation cycle.

Check your 23andMe results for rs4986782:

  • AA: NAT1*14B, slow acetylator [ref]
  • AG: slow acetylator,
  • GG: normal

 

Check your 23andMe results for rs15561:

  • AA: reduced function [ref]
  • AC: reduced function
  • CC: normal

 

Check your 23andMe results for rs6586714:

  • AA: lower risk of colon cancer from cooked meat carcinogens (protective) [ref]
  • AG: lower risk of colon cancer from a cooked meat carcinogens
  • GG: wildtype/common

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]

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

Further reading:

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

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