How The CYP2E1 Gene Influences Detoxification And Drug Clearance

CYP2E1 Enzyme

The CYP2E1 enzyme is a part of the Cytochrome P450 family and plays a role in drug metabolism.

Drug metabolism is the process by which the body breaks down pharmaceutical drugs and other chemicals from the system using enzymatic systems. Drug metabolism can make the drug more active, inactive, or convert it into a more toxic metabolite (intermediary substance).

This enzyme makes up less than 1% of the total CYP450 enzymes and helps in clearing 2% of the total prescription drugs in the market.

CYP2E1 is mostly concentrated in the liver. It is also found in the lungs, brain, and kidney.

There are many variations (changes) in the CYP2E1 gene. These genetic variations create a difference in drug metabolism and increase/decrease the risk of different health conditions like diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), liver inflammation, and cancer.

Substances That The CYP2E1 Gene Act On

The CYP2E1 enzyme can activate small, low molecular weight compounds. Some of them include:

Ethanol

Ethanol is a simple alcohol that is commonly used as a food additive. It is the basic ingredient in most types of alcohol like wine, beer, and brandy. It is also added in food colors to evenly distribute the color. Ethanol is added to varnish and household cleaning products too.

The CYP2E1 enzyme is responsible for ~20% of ethanol metabolism in the brain.

Acetone

Acetone is a flammable colorless liquid that is commonly used as thinners and nail polish removers. Internally, acetone is produced as a result of various metabolic activities in the body. The CYP2E1 enzyme eliminates excess acetone from the body and prevents acetone toxicity.

Fluorinated anesthetics

Inhalational anesthetics are administered using a face mask. Such anesthetics are made stronger and safer by adding fluorine to them. Below are some fluorinated anesthetics.

Methoxyflurane
Sevoflurane
Enflurane
Isoflurane
Desflurane

The CYP2E1 enzyme plays a role in the metabolism of most of these fluorinated anesthetics.

Benzene

Benzene is a sweet-smelling chemical that is flammable. Benzene is both man-made and naturally occurring. Naturally, benzene is released during forest fires and volcanic eruptions. Benzene is also a side-product released during the production of pesticides, lubricants, and rubber.

Over-exposure to benzene leads to anemia and certain types of cancers.

The CYP2E1 converts benzene into benzene dioxide and plays a role in clearing the toxin from the body.

N-nitrosodimethylaminen

N-nitrosodimethylaminen is also called dimethylnitrosamine (DMN), and this is produced as a result of chlorine water treatment. DMN is also found in cured meat and fish. Inhaling tobacco products increases the risk of DMN exposure too.

CYP2E1 metabolizes DMN in the body.

Acrylamide

Acrylamide is a chemical released when food is roasted, baked, or fried at very high temperatures. The chemical is found more in starchy foods like potatoes. This chemical is highly toxic and can increase the risk of developing cancer.

CYP2E1 metabolizes acrylamide in the body and prevents its build-up in the body.

4-nitrophenol

4-nitrophenol is a chemical used in the manufacturing of pesticides, fungicides, dyes, and leather. People who work in these manufacturing units are at high risk for 4-nitrophenol exposure. Exposure to this chemical can lead to nausea, drowsiness, and headaches. The long-term effects of exposure to this chemical are still being researched. The CYP2E1 enzyme metabolizes this chemical in the body.

Acetaminophen

Acetaminophen is a pain-reliever. It is also commonly called paracetamol. This drug is used in treating fever and mild body aches. The CYP2E1 enzyme metabolizes acetaminophen and converts it into a more toxic form called N-acetyl-p-benzoquinone imine (NAPQI).

Acetaminophen Hepatotoxicity

Hepatotoxicity is also called toxic hepatitis and causes serious liver damage. CYP2E1 encourages acetaminophen hepatotoxicity. NAPQI, in large amounts in the body, can lead to cellular damage. NAPQI needs to be quickly removed from the body with the help of glutathione or converted back to acetaminophen.

CYP2E1 Inducers and Inhibitors

Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.

Drugs that Induce CYP2E1 Activity

Isoniazid - Isoniazid, an antibiotic, is a common drug used to treat tuberculosis. It is an inducer of CYP2E1.
Ethanol - Ethanol is present in all types of alcohol and is an inducer of the CYP2E1 enzyme. When a person drinks excessive alcohol, the body produces an excess of the CYP2E1 enzyme to increase ethanol metabolism.
Pyrazole - Pyrazole is used in the production of many Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). It is an inducer of the CYP2E1 enzyme.

Drugs that Inhibit CYP2E1 Activity

Chlorzoxazone - Chlorzoxazone is a muscle relaxant that helps handle different musculoskeletal conditions. It is used in treating muscle spasms and pain and is a strong inhibitor of CYP2E1.
Disulfiram - Disulfiram is a drug used to treat alcohol abuse and helps create strong sensitivity to alcohol (ethanol). This is an inhibitor of CYP2E1.
Indazole - Indazole is a part of many drug molecules, including anti-inflammatory drugs and chemotherapy drugs. Indazole is a CYP2E1 inhibitor.
4-methylpyrazole (Fomepizole) - This is a drug used to treat methanol poisoning and ethylene glycol poisoning. Fomepizole is also an inhibitor of the CYP2E1 enzyme.

Variations In The CYP2E1 Gene

There are multiple variations in the CYP2E1 gene that influence the activity of the CYP2E1 enzyme.

Haplotype	Effect
CYP2E1*2	Decreased enzyme activity
CYP2E1*6/CYP2E1_marker9	Increased enzyme activity
CYP2E1*7B	Increased enzyme activity
CYP2E1 *5B	Increased enzyme activity

A haplotype is a group of gene changes that are inherited together. The *2, *6, *5B, and *7B are all star alleles. Star alleles are used to name different haplotypes.

Recommendations To Boost CYP2E1 Metabolism

Foods that Induce CYP2E1 Enzyme Activity

Foods rich in omega-3 fatty acids induce CYP2E1 levels in the body.

Some food sources of omega-3 fatty acids are:

Fatty fish
All kinds of seafood
Nuts and seeds
Plant-based oils
Avocados

Foods that Inhibit CYP2E1 Enzyme Activity

Here is a list of foods that inhibit CYP2E1 activity.

Starfruit
Garlic
Antioxidant-rich black and green tea
Turmeric
Garlic
Black pepper
Kale, cherry tomatoes, blueberries, and broccoli - rich in quercetin, a type of flavonoid (plant-based antioxidant)
Watercress

Vitamins and Minerals That Support CYP2E1 Enzyme Activity

Both Vitamin C and vitamin E prevent oxidative stress and lipid peroxidation (free radicals damage the lipids in cell membranes, leading to cell damage) in the body. These vitamins also prevent a decrease in the CYP2E1 enzyme activity in the liver and improve CYP2E1 drug metabolism.

Genetic Testing

Genetic testing can help identify the metabolizer status of an individual for a gene (or group of genes) or a drug (or group of drugs). Depending on the genetic results, doctors can then plan drug dosages and opt for safer medications.

Summary

The CYP2E1 gene helps produce the CYP2E1 enzyme. This enzyme is responsible for clearing 2% of all the prescription drugs sold in the market.
The CYP2E1 enzyme is an important enzyme involved in the metabolism of ethanol.
Certain drugs like isoniazid, ethanol, and pyrazole can induce CYP2E1 activity in the body. Drugs like Chlorzoxazone, Disulfiram, Indazole, and Fomepizole inhibit the CYP2E1 activity.
The *2, *6, *5B, and *7B haplotypes of the CYP2E1 gene decrease or increase the enzyme activity. This can lead to drug overexposure or increased levels of toxic intermediates.
Genetic testing can be used to learn more about your enzyme levels.