Once toxins are initially broken down in the body, they must be converted to a water-soluble molecule in order to be excreted. Genetic variants in the NAT genes significantly influence the cancer risk due to toxicants, including cigarette smoke.
NATs: N-acetyltransferase
N-acetyltransferase is a phase II detoxification enzyme getting rid of several types of toxicants.
This enzyme helps your body eliminate 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 drugs. A significant percentage of people were found to be poor acetylators resulting in significant side effects of the tuberculosis drug, isoniazid.
NAT1:
NAT1 metabolizes p-aminobenzoic acid (PABA) and p-aminosalicylic acid (PAS).[ref] PABA is 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 form when meats and seafood are grilled at high temperatures.
Studies link NAT1 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 riskier 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 are 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 when pregnant.[ref] Both of those conditions are linked to folate metabolism and the methylation cycle.
NAT2:
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 of several types of cancers.
NAT1 Genotype Report:
NAT1:
Check your genetic data for rs4986782 (23andMe v4, v5):
- A/A: NAT1*14B, slow acetylator[ref]
- A/G: slow acetylator
- G/G: typical
Members: Your genotype for rs4986782 is —.
Check your genetic data for rs15561 (23andMe v4):
- A/A: reduced function[ref]
- A/C: reduced function
- C/C: typical
Members: Your genotype for rs15561 is —.
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 cooked meat carcinogens
- G/G: typical
Members: Your genotype for rs6586714 is —.
There are several other SNPs that are not included in 23andMe data, so the above SNPs are not the complete picture for NAT1.
NAT2:
Check your genetic data for rs1495741 (23andMe v4, v5; AncestryDNA):
- A/A: likely NAT2 slow metabolizer [ref]
- A/G: likely NAT2 intermediate metabolizer
- G/G: likely NAT2 rapid metabolizer
Members: Your genotype for rs1495741 is —.
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