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NAT1 and NAT2: N-acetyltransferases and phase II detoxification

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:

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Lifehacks for NAT1 and NAT2:

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

Cut back on fried foods and grilled meats: 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

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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 from Colorado School of Mines 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.