What Is Acetylation?
Acetylation is a part of the phase 2 detoxification pathway and helps eliminate various harmful substances from the body. The N-acetyltransferase (NAT) enzymes are responsible for acetylation. The NAT enzymes are also called arylamine N-acetyltransferases.
The NATs transfer a molecule called acetyl CoA to the toxins to make them less harmful and to eliminate them easily from the body. In some cases, the NATs can also convert substances into their more active (toxic) forms and send them to the next detoxification stage. Such active forms have to be quickly eliminated from the body.
Importance of Acetylation
Acetylation is majorly associated with the detoxification of xenobiotics (foreign substances found in the body). They help transform xenobiotics that enter the body by either making them less harmful or more harmful.
For certain xenobiotic substances, acetylation is the only available detoxification pathway. Problems with acetylation will cause an excess accumulation of these substances in the body and lead to an increased risk of cancers and other health conditions.
Melatonin is a hormone produced in the body by the pineal glands. The hormone controls the sleep-wake cycle and helps prevent sleep disorders. Acetylation converts serotonin into melatonin and hence is essential to improve your sleep.
Some studies suggest that NATs may play a role in folate metabolism (the process of converting folate into a form usable by the body). There seems to be an inverse relationship between folate levels in the body and NAT activity.
N-alpha-acetyltransferases - NAT1 and NAT2
There are two major types of NATs produced in the body - NAT1 and NAT2.
The NAT1 gene produces the NAT1 enzyme. The NAT1 enzyme is primarily found in the extrahepatic tissues (tissues found outside the liver). This enzyme is essential for folate metabolism and in the biotransformation of the following.
- p-aminobenzoic acid (PABA)
- p-aminobenzoyl glutamate
- p-aminosalicylic acid (PAS)
The NAT2 gene produces the NAT2 enzyme. The NAT2 enzyme is primarily found in the gut and the liver. This enzyme activates and deactivates a variety of substances, including hydrazines and arylamines.
Some compounds like 2-aminofluorene need to be eliminated with the help of both NAT1 and NAT2.
Changes in the functioning of the NAT1 and NAT2 genes (genetic polymorphisms) can affect the body’s capacity to add an acetyl group to the above toxins. Based on how an acetyl group is added to xenobiotics, there are three types of NAT metabolizers identified.
- Slow metabolizers
- Normal metabolizers
- Fast metabolizers
Slow metabolizers cannot quickly eliminate toxins from the body, which leads to toxic buildup and an increased risk of different types of cancer.
Fast metabolizers quickly process prescription drugs and eliminate them before they can do their job. As a result, fast metabolizers may need extra dosages of medications for treatment.
A particular population study suggests that 8% of people may be slow NAT1 metabolizers.
Effects of fast NAT metabolism
Studies suggest that fast NAT2 metabolism may increase a person’s risk for developing Alzheimer’s disease.
Fast NAT2 metabolism also increases the risk of colorectal cancer in those exposed to an excess of tobacco smoke in their lifetime.
N acetyltransferase deficiency occurs as a result of low levels of NAT enzymes in the body. This decreases the acetylation process of xenobiotics and leads to increased levels of toxicity of foreign substances. NAT deficiency can lead to the following problems.
- Isoniazid toxicity - Isoniazid (INH) is a very common antibiotic used in treating various bacterial infections. Studies show that INH may entirely depend on NATs to get eliminated from the body. NAT deficiency can lead to INH hepatotoxicity (liver toxicity).
- Sulfonamide toxicity - Sulfonamides contain sulfa drugs. These are also commonly prescribed antibiotics. People with NAT deficiency (slow metabolizers) are at a higher risk for developing sulfonamide toxicity.
- Occupational bladder cancer - Occupational bladder cancer is a result of excessive exposure to arylamines in the workplace. Smoking also increases arylamine exposure. Slow NAT metabolism or N acetyltransferase deficiency can increase the risk of occupational bladder cancer.
- Breast cancer - Studies suggest that in postmenopausal women who were current and past smokers, slow acetylators had an increased risk of breast cancer.
According to MalaCards, an integrated database of human maladies, NAT deficiency can increase the risk of the following health conditions.
- Mucopolysaccharidosis type iii C (An inherited condition with the inability to breakdown monosaccharides, a kind of sugar molecule)
- Papillomatosis (presence of multiple benign lumps in the skin)
Genetic Variations of the NAT1 and NAT2 genes
Genetic variations (genetic polymorphisms) of the NAT1 and NAT2 genes can increase or decrease NAT1 and NAT2 enzyme activities.
|NAT1*10||Increased enzyme activity||Protection against various xenobiotic toxicities|
|NAT1*11||Increased enzyme activity||Protection against various xenobiotic toxicities|
|NAT2*6B||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
|NAT2*5D||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
|NAT2*7A||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
|NAT2*11A||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
|NAT2*12A||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
|NAT2*13A||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
|NAT2*14A||Decreased enzyme activity||Increased risk of drug and chemical toxicity and cancer|
Cholangiocarcinoma is cancer in the bile duct. Studies show that people with NAT2*13, NAT2*6B, and NAT2*7A haplotypes had a decreased risk for cholangiocarcinoma while people with the NAT2*4, *5, *6A, and *7B haplotypes did not have such a protective effect.
Substances that undergo Acetylation
- Arylamines - Arylamines are organic chemicals used to produce polymers, fungicides, pesticides, rubber, and cosmetics. Arylamines are also present in tobacco smoke, house fumes, and automobile exhaust.
- Hydrazine - Hydrazine is an inorganic chemical that is used majorly as a space vehicle propellant. It can reach the body through ingestion, inhalation, and absorption through the skin cells. This chemical is also found in small quantities in cigarette smoke. According to the U.S. Environmental Protection Agency (EPA), hydrazine is a possible human carcinogen (cancer-causing agent).
- Heterocyclic Aromatic Amines (HAAs) - These are chemicals found in foods, especially meat, that are burnt or charred while cooking. HAAs are considered possible carcinogens.
- Carcinogens from cigarette smoke - Acetylation helps eliminate various other cancer-causing agents inhaled through cigarette smoke.
- Environmental carcinogens - Acetylation transforms various other environmental toxins that can cause harm to the body into a more inactive form and helps in their elimination.
- Common drugs - Many common drugs go through acetylation. Few common ones are listed below.
- Hydralazine - to treat high blood pressure
- Isoniazid - to treat tuberculosis
- Sulphonamides - to treat bacterial infections
- Clonazepam and nitrazepam - to treat seizures, movement disorders, and anxiety
- Dapsone - to treat inflammation
Recommendations To Boost NATs
Smoking is harmful in many ways. Smoking increases the risk of developing lung cancer in people who are slow NAT metabolizers. Both occasional smoking and second-hand smoking equally increases the risk.
Consider Vitamin C supplements
Vitamin C, when orally consumed, can increase NAT activity in the body. This can help nullify the effects of carcinogenic xenobiotics that enter the body. Vitamin C supplements can hence decrease the risk of cancers.
Change to a Mediterranean diet
A Mediterranean diet is a diet rich in fresh fruits and vegetables, fresh seafood, whole grains, extra virgin olive oil, and minimally processed foods, sugar, refined grains, and red meat. This is an antioxidant-rich diet.
Chemoprotective nutrients like antioxidants can induce NAT enzymes in the body and can bring down the risk of developing cancers.
Stay away from substances that inhibit NATs
Certain natural substances can inhibit NAT activity in the body. Therefore, if you are a slow NAT metabolizer, you should stay away from these substances.
- Caffeic acid - This is a type of polyphenol that has antioxidant and anticancer properties. It is found in most types of plants.
- Quercetin - Quercetin is a flavonoid with antioxidant properties.
- Genistein - Genistein is a type of plant flavonoid with antioxidant properties.
- Coumarin - Coumarin is a colorless organic substance that has a sweet vanilla smell and is a plant-derivative.
- Garlic - Garlic contains diallyl sulfide and diallyl disulfide that can inhibit NAT activity
Genetic testing will tell you if you are a slow, normal, or fast NAT metabolizer. The genetic testing results will help your doctor recommend ways to improve the acetylation process and bring down the risk of cancers.
- Acetylation is a part of phase 2 detoxification. The N-acetyltransferase (NAT) enzymes are responsible for acetylation.
- In acetylation, an acetyl Co-A molecule is added to toxins to either make them less active or to convert them into a more active intermediate form.
- NAT1 and NAT2 are the two major NAT enzymes in the body. Changes in the NAT1 and NAT2 genes can lead to increased or decreased enzyme activities.
- Depending on how effectively acetylation happens, people can be slow metabolizers, normal metabolizers, or fast metabolizers.
- Increased enzyme activity may protect against cancers but can prevent prescription drugs from working effectively. Decreased enzyme activity may lead to an increased risk of different types of cancers.
- N-acetyltransferase deficiency causes drug toxicity, occupational bladder cancer, and breast cancer.
- Smoking increases the risk of developing cancer in slow NAT metabolizers. Vitamin C supplements may help increase NAT activity in the body and are beneficial. A Mediterranean diet may also help bring down the risk of breast cancer in slow metabolizers.