Oxidative stress is an imbalance in the production of free radicals and antioxidants in the body.
Free radicals are atoms or molecules that contain unpaired electrons. They are formed when oxygen reacts with certain molecules.
The unpaired electrons stabilize themselves by attacking other molecules and poaching their electrons.
They are called Reactive Oxygen Species (ROS).
Some of the common types of free radicals are:
Free radicals cause cellular damage by altering cell structures like DNA, proteins, lipids, and lipoproteins.
Antioxidants are molecules that neutralize free radicals by donating one of their electrons to the free radicals. Antioxidants are both produced in the body and obtained through food.
Antioxidants can prevent or delay cellular damage.
Oxidative stress happens when the number of free radicals is more than the number of antioxidants.
Oxidative stress can lead to cellular level damage and various chronic and degenerative conditions like:
Detoxification is a natural process to help eliminate harmful toxins, chemicals, drugs, and other substances from the body.
The Cytochrome P450 (CYP) enzymes play a significant role in phase I detoxification. These enzymes add a reactive group to endogenous (produced inside the body) and exogenous (originated outside the body) chemicals, toxins, drugs, and other substances in the body to metabolize them.
The common reactive groups added are hydroxyl, carboxyl, or amino. After adding these reactive groups, these endogenous and exogenous substances are converted into more active forms. These active forms are called intermediate metabolites. The conversion of each molecule of these endogenous and exogenous substances into their intermediate metabolite forms releases free radicals.
The free radicals, in turn, cause cellular level damage and oxidative stress.
CYP enzyme-induced oxidative damage leads to physical damage in the body, increasing the risk of cancer, diabetes, and cardiovascular problems.
Superoxide dismutase 2, mitochondrial (SOD2) gene provides instructions for the production of the SOD2 enzyme. This enzyme is an antioxidant and helps in converting superoxide radicals (O2•−) into oxygen (O2) and hydrogen peroxide (H2O2).
Superoxide is a compound that contains the superoxide ion.
rs4880 is a Single Nucleotide Polymorphism (SNP) in the SOD2 gene.
People with the GG genotype of this SNP have a lower SOD2 enzyme activity compared to those with the AA and GA genotypes.
This increases their risk of:
|GG||Lower SOD2 enzyme activity and increased risk of oxidative stress|
|GA||Normal SOD2 enzyme activity and regular risk of oxidative stress|
|AA||Normal SOD2 enzyme activity and regular risk of oxidative stress|
The Catalase (CAT) gene provides instructions for the production of the catalase enzyme. This enzyme is also an antioxidant and converts hydrogen peroxide (H2O2) into oxygen (O2) and water (H2O).
rs1001179 is an SNP in the CAT gene. The T allele of this gene is associated with an increased risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.
|T||Increased risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.|
|C||Normal risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.|
The glutathione peroxidase 1 (GPX1) gene provides instructions for the production of an enzyme belonging to the glutathione peroxidase family. This enzyme plays a role in converting hydrogen peroxide into water and oxygen, thereby protecting the body from hydrogen peroxide-induced oxidative stress.
rs1050450 is an SNP in the GPX1 gene. People with the TT genotype of this SNP have increased mortality rates due to aging compared to people with the CC and CT genotypes. Oxidative stress is one of the key reasons for aging and mortality related to aging.
|TT||Increased mortality rate due to aging|
|CC||Decreased mortality rate due to aging|
|CT||Decreased mortality rate due to aging|
The NAD(P)H quinone dehydrogenase 1 (NQO1) gene provides instructions for the production of the NQO1 enzyme. This is a vital antioxidant enzyme that plays a role in preventing oxidative stress and activating vitamin E and vitamin K.
This enzyme also helps maintain the right CoQ10 levels. CoQ10 or Coenzyme Q10 is a nutrient with immense health benefits in the body and acts as an antioxidant to prevent oxidative damage.
rs1800566 is an SNP in the NQO1 gene. People with the A allele of this SNP have a higher risk of oxidative stress than those with the G allele.
|A||Higher risk of oxidative stress|
|G||Lower risk of oxidative stress|
NAC is a Food and Drug Administration (FDA) approved antioxidant made from the L-cysteine amino acid. Studies show that glutathione is an important antioxidant needed to fight free radicals. Phase 1 detoxification depletes glutathione levels and increases the risk of free radical oxidative stress.
NACs can restore glutathione levels. Your healthcare provider should be able to prescribe NAC for you.
Some studies show that planned calorie restriction (without the risk of malnutrition) can bring down the effect of oxidative stress in the body.
Fruits and vegetables have high levels of antioxidants. Therefore, include 3-5 servings of the below fruits and vegetables every day in your diet.
Regular moderate exercise can bring down oxidation damage and increase antioxidant activity in the body. Ensure you get at least 150 hours of moderate exercise/week to reduce the risk of oxidative stress.
When your body is exposed to excessive chemicals, drugs, and other toxins, the CYP enzymes have to work harder to eliminate them. As a result, more intermediate metabolites and free radicals are produced.
You can bring down the risk of oxidative stress by avoiding exposure to substances including:
Genetic testing can help understand a person’s risk of oxidative stress. This can help predict future chronic and degenerative diseases and take preventive actions in the present.
The CYP2J2 gene contains instructions for the production of the cytochrome P450 2J2 enzyme. This enzyme is found in the extrahepatic tissues (tissues located outside the liver), especially in the gastrointestinal tract, kidneys, lungs, pancreas, and brain.
The CYP2J2 enzyme is called an oxygenase. This is because it breaks down xenobiotics (substances not usually expected to be found in the body), cholesterol, fatty acids, and numerous other chemicals by adding an oxygen molecule to them.
CYP2J2 is especially important in arachidonic acid (AA) metabolism. AA is a polyunsaturated omega-6 fatty acid found in organ meat, poultry, eggs, seafood, and seaweed.
The CYP2J2 enzyme converts AA into four epoxyeicosatrienoic acids (EETs). EETs are types of signaling molecules that have various positive effects on the body.
EETs may be able to:
The CYP2J2 enzyme metabolizes many drugs.
Ebastine is an antihistamine drug used to treat signs of allergies, including sneezing, swelling, itching, and rashes.
Astemizole is also an antihistamine drug that provides long-term relief to allergy symptoms.
Terfenadine is also an antihistamine drug used to treat allergic symptoms.
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used to treat inflammatory conditions like gout and arthritis.
Perphenazine is an antipsychotic drug used in treating mood disorders, including schizophrenia, bipolar disorder, and symptoms like hallucinations and aggressive behavior.
Budurarol is a non-selective adrenoceptor blocking agent that has antiarrhythmic properties. It reduces heart rate, stabilizes blood pressure, and helps protect cardiac health.
Doxorubicin is an anti-cancer drug and is used in chemotherapy. Doxorubicin, in higher doses, may lead to cardiotoxicity and heart failure. Studies show that higher levels of CYP2J2 enzyme may prevent doxorubicin toxicity and protect the heart.
Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.
Inducers speed up the activity of the CYP2J2 enzyme, leading to quicker metabolism of the xenobiotics and drugs that the enzyme acts on. As a result, the drugs don’t get enough time to work.
Here is a list of drugs that induce CYP2J2 activity.
Inhibitors slow down the activity of the CYP2J2 enzyme, resulting in slower metabolism of xenobiotics and drugs that the enzyme acts on. As a result, the drug stays in circulation for a longer time, and there is an increased risk of a drug overdose.
Here is a list of drugs that inhibit CYp2J2 activity.
There are many types or variations of CYP2J2, the most well-studied being the CYP2J2*7 haplotype.
A haplotype is a group of gene changes that are inherited together. *7 is called a star allele. Star alleles are used to name different haplotypes.
A study shows that in the Caucasian population, the CYP2J2*7 allele leads to a 40% reduction in the CYP2J2 enzyme levels. This can increase the risk of developing cardiovascular diseases like myocardial infarction, ischemic stroke, and atherosclerosis.
Two Single Nucleotide Polymorphisms (SNPs) - rs10889160 and rs11572325 in this gene have been associated with an increased risk of myocardial infarction.
People with the G and A alleles of the SNPs rs10889160 and rs11572325, respectively, have a 1.24 and 1.27-fold increased risk of developing myocardial infarction than those with the A and T alleles.
|rs10889160||G||1.24-fold increased risk of developing myocardial infarction|
|rs11572325||A||1.27-fold increased risk of developing myocardial infarction|
A case-controlled study analyzed the relationship between variations in the CYP2J2 gene and the risk of developing Chronic Obstructive Pulmonary Disease (COPD).
People with the T allele of the SNP rs1155002 had an increased risk of developing COPD, while people with the T allele of the SNP rs2280274 had a decreased risk.
In addition, being a female and smoking further increased the risk.
|rs1155002||T||Increased risk of developing COPD|
|rs2280274||T||Decreased risk of developing COPD|
BHA is a preservative added to many food products. It is a food-based antioxidant to prevent oxidative damage to oils and fats. It keeps oil and fat-based foods fresher for a longer time. BHA is found in foods like the below.
BHA can induce CYP2J2 activity. Therefore, if you are on drugs metabolized by CYP2J2, limit intake of the above foods to prevent faster metabolism of the drugs.
If you are on specific drugs that inhibit CYP2J2 activity, consult your doctor and understand the effects on the body. Combining medications metabolized by the CYP2J2 enzyme and these CYP2J2 inhibitors may lead to a drug overdose.
Genetic testing will help understand how protective the CYP2J2 gene variations are against cardiovascular diseases. This can play a role in predicting heart conditions in the future.
Cytochrome P450 Family 3 Subfamily A Member 4 or CYP3A4 gene belongs to the cluster of cytochrome P450 genes and is located on chromosome 7.
The family of Cytochrome P450 gene gives instructions for the production of enzymes that are responsible for the metabolism (the process by which drugs are broken down or chemically altered by the body to bring about the effect) of drugs, hormones, and other xenobiotics (substances not produced by the body).
The CYP3A4 gene produces the CYP3A4 enzyme that belongs to a group of monooxygenases (enzymes that contain one oxygen atom). It is involved in the metabolism of nearly 50% to 60% of the currently prescribed drugs, including acetaminophen, codeine, cyclosporin A, diazepam, etc.
The CYP3A4 gene is also involved in the production of cholesterol, steroids, and other lipids (fats).
Along with the CYP3A5 gene, the CYP3A4 gene is found predominantly in the liver.
There are over 20 variants (types) of the CYP3A4 gene that have been studied. Based on the presence of the CYP3A4 variant people carry, they can be classified as:
The *22, *1, *29, *15, etc., mentioned above are star alleles. Star alleles are used to name different haplotypes. A haplotype is a group of gene changes that are inherited together (CYP3A4*20, CYP3A4*1).
Inducers speed up the activity of the CYP3A4 enzyme, leading to quicker metabolism of the substances that the enzyme acts on.
Some drugs that increase or induce CYP3A4 activity are:
Apart from drugs, some insecticides and pesticides are also known to induce CYP3A4 genes. These include
Inhibitors slow down the activity of the CYP3A4 enzyme, resulting in the slower metabolism of substances that the enzyme acts on.
Some drugs inhibit or reduce CYP3A4 activity, and these include:
CYP3A4 gene inhibitor drugs can be classified based on their potency as – strong, moderate, or weak inhibitors.
CYP3A4 has fewer variants (types) than other CYP genes, and only a few of them are known to affect enzyme function. There are around 20 variants of this gene that have no clinical significance. Few significant variants include CYP3A4 *22, *1B, and *18B.
Also referred to as rs35599367, people with the T allele of this haplotype show decreased CYP3A4 enzyme activity. This haplotype is found in 4% to 8% of the population.
Studies show that people with T/T allele had two times lower enzyme activity than those with the C allele. This is important because people having the T/T genotype require a 40% lower dose of simvastatin (a cholesterol-lowering drug).
Children with the CYP3A4*22 variant show improved asthma control by taking fluticasone propionate (a drug used to treat asthma).
Research also states that CYP3A4*22 carriers were less likely to suffer from severe hot flashes on taking tamoxifen therapy (used for breast cancer).
rs2740574 is a single nucleotide polymorphism or SNP in the CYP3A4 gene. The presence of the G allele in this SNP in this gene is known as CYP3A4*1B.
The *1B haplotype may be associated with methadone overdose and fatal intoxication.
The G allele of this haplotype also increases the risk for prostate, ovarian, and lung cancers.
Also denoted as rs2242480, this variant of the CYP3A4 gene affects fentanyl (an opioid pain medication) dosage. Research states that patients with *18B/*18B alleles required lesser fentanyl dosage to control pain than patients with *1/*1 genotype.
Some interactions of the CYP3A4 gene with herbal medicines and food can reduce its metabolic effect.
Therefore, most doctors take a thorough history of all medications, herbal supplements, or alternative medicines that you may be taking to avoid any adverse reactions and prevent reduced CYP3A4 metabolism.
Genetic testing may be advised before prescribing drugs that are metabolized by the CYP3A4 gene. This is particularly true while prescribing simvastatin, fluticasone propionate (in children), tamoxifen, methadone, and fentanyl.
The Cytochromes P450 (CYPs) are a group of enzymes that play an important role in the detoxification process. Detoxification is a process by which toxins and unwanted substances are removed from the body. There are three stages of detoxification, and CYPs help in phase 1 detoxification.
According to the Human Genome Project, 57 different types of CYP enzymes are identified in human beings.
The CYP1 group of enzymes is a major part of the CYP family. The Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) is one of the three CYP1 enzymes that help in detoxification. This enzyme is majorly found in the lungs.
The CYP1A1 gene helps produce the CYP1A1 enzymes.
Xenobiotic substances are those that reach the body from external sources. These are not produced or found internally. The CYP1A1 enzymes work on removing Polycyclic Aromatic Hydrocarbons (PAHs) from the body.
PAHs are groups of chemicals found throughout the environment, in the air, soil, and water. PAHs are produced when fossil fuels like coal, gasoline, and oil are burnt.
These are also produced when tobacco and wood are burnt. PAHs are common toxins in charred and burnt meat. There are hundreds of PAHs in the atmosphere. Few common ones are:
Endogenous substances are those that are produced or available in the body. The CYP1A1 enzyme helps in the metabolism of certain endogenous substances.
Polyunsaturated Fatty Acids or PUFAs
The CYP1A1 enzyme converts PUFAs into signaling molecules. These signaling molecules are needed for various bodily functions.
CYP1B1 enzyme converts arachidonic acid, a type of PUFA, into 19-hydroxyeicosatetraenoic acid (19-HETE). 19-HETE controls high blood pressure and the growth of cancer cells.
CYP1A1 enzymes play a role in 17β-estradiol metabolism. 17β-estradiol is an estrogen hormone. This is responsible for regulating the female reproductive system.
Oxidative stress is a condition where the number of free radicals in the body is higher than the number of antioxidants. This imbalance leads to cell damage and an increased risk of cancer and other diseases. Some studies show that the CYP1A1 enzymes fight against Reactive Oxygen Species (ROS) and prevent oxidative stress.
Multiple changes or variations in the CYP1A1 gene lead to increased or decreased CYP1A1 enzyme activity. These gene variations protect against or increase the risk of conditions like cancer, PolyCystic Ovary Syndrome (PCOS), and diabetes.
|CYP1A1*2C||Increased enzyme activity||CYP1A1 enzyme at higher levels can accelerate phase 1 detoxification and result in increased production of free radicals.|
|CYP1A1*2A||Increased enzyme activity||CYP1A1 enzyme at higher levels can accelerate phase 1 detoxification and result in increased production of free radicals.|
Overactive CYP1A1 enzymes can result in free radical damage. This can be treated with an antioxidant-rich diet. The following are some great sources of antioxidants:
- Fresh fruits and vegetables
- Nuts and seeds
- Spices and herbs
The Polycyclic Aromatic Hydrocarbons (PAHs) in tobacco in cigarettes increase CYP1A1 enzyme levels. Overactivity of the enzyme leads to quick phase 1 detoxification and increased free radical damage in the body. Quit smoking to bring down the risk of cancers and other diseases.
CYP1A1 genetic testing can help you identify changes in your CYP1A1 gene. This can give some insights into your CYP1A1 enzyme levels. If you have increased levels of this enzyme, your doctor may ask you to get screened for different types of cancers frequently. A genetic counselor can also help you interpret the report and understand it better.
1. The Cytochromes P450 (CYPs) enzymes play a role in phase 1 detoxification. CYP1A1 is one of the important enzymes in this group.
2. The CYP1A1 enzyme helps with the metabolism of toxins like Polycyclic Aromatic Hydrocarbons (PAHs) and certain hormones and fatty acids in the body.
3. Certain changes in the CYP1A1 gene can increase the activity of the CYP1A1 enzyme. As a result, the phase 1 detoxification stage occurs quickly, increasing free radical molecules in the body.
4. Free radicals can damage DNA and lead to an increased risk of many types of cancer, including breast, biliary, and lung cancer.
5. Including an antioxidant-rich diet plan can help prevent free radical damage.
6. In people with high CYP1A1 enzyme levels, smoking can increase the risk of free radical damage and can cause cancers in the breast, lungs, liver, and cervix.
7. Genetic testing can give you insights into your CYP1A1 enzyme levels. For people with errors in the CYP1A1 gene, regular screening of cancer is recommended.
The CYP1B1 enzyme is a part of the Cytochrome P450 (CYPs) family and was first identified in 1994. The CYP family is a group of enzymes that play a major role in detoxification in the body.
This enzyme helps in the metabolism and clearance of the various endogenous (produced internally) and exogenous (produced externally) substances.
It is especially important for metabolizing cancer-causing agents (procarcinogens) like 17 beta-estradiol (an estrogen hormone) and Polycyclic Aromatic Hydrocarbons (PAHs). This enzyme is also responsible for adding oxygen atoms to other molecules.
This enzyme is produced in many tissues in the body, including the eyes. The CYP1B1 gene controls the production of the CYP1B1 enzyme. Certain changes (or mutations) in this gene can lead to overproduction or insufficient production of the enzyme and lead to diseases like primary congenital glaucoma.
The CYP1B1 enzyme helps in processing polyunsaturated fatty acids and fat-soluble vitamins like vitamins A, D, E, and K.
The CYP1B1 enzyme is the most important enzyme required for 17 beta-estradiol (E2) metabolism. Metabolism is the process by which large and complex food molecules and medicines are broken down into smaller components to produce energy, build or repair body tissues, produce hormones, and do more such activities needed for the body. This hormone is responsible for the female reproductive system management. High levels of E2 in the body can increase the risk for breast, ovarian, and uterine cancer.
Melatonin is a natural hormone found in the human body. Melatonin is secreted at night by the pineal glands and controls the sleep-wake cycle. Recent studies have identified that melatonin kills certain types of cancer cells in the body - melatonin has anti-cancer properties. The CYP1B1 enzyme helps in the transformation of melatonin into N-acetylserotonin (NAS). NAS helps destroy cancer cells.
PAHs are chemicals commonly found in certain natural sources like fossil fuels and many man-made products like toiletries, tobacco, garbage, and different plastic and rubber products. PAH is also produced when meat and other kinds of food are cooked at high temperatures and charred. PAHs are air-bound and enter the body when people breathe.
Both the CYP1A1 and the CYP1B1 enzymes help convert PAHs into a more active form in the phase 1 detoxification stage. With more exposure to PAHs, the body produces more CYP1B1 enzymes, and more free radicals are produced. This increases the risk of cancers.
Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.
There are many drugs that inhibit CYP1B1 activity. Some of them are:
CYP1B1 enzymes, produced by the CYP1B1 gene, protect the body from oxidative stress. Oxidative stress is caused due to increased free radicals in the body, resulting in cell damage. Changes in the CYP1B1 gene can decrease or increase the levels of the CYP1B1 enzyme produced.
|CYP1B1*2||Increased enzyme activity||Increased risk of oxidative stress and different types of cancer|
|CYP1B1*3||Increased enzyme activity||Increased risk of oxidative stress and different types of cancer|
|CYP1B1*4||Increased enzyme activity||Increased risk of oxidative stress and different types of cancer|
|CYP1B1*12||Decreased enzyme activity||Lowered risk of oxidative stress and different types of cancer|
A haplotype is a group of gene changes that are inherited together. The *2, *3, *4, and *12 are star alleles. Star alleles are used to name different haplotypes.
Certain foods can encourage high levels of estrogen production in the body. To process high estrogen levels, the body produces an excess of the CYP1B1 enzyme.
This can lead to a high risk for different types of cancers, including breast cancer, ovarian cancer, and uterine cancer.
The foods listed below can naturally bring down estrogen metabolism in the body.
Cigarettes contain multiple Polycyclic Aromatic Hydrocarbons (PAHs) and various other chemicals. Smoking encourages PAH-DNA adduct formation in the lungs. PAH-DNA adduct is the accumulation of genetic changes in the DNA cells, leading to the formation of cancerous cells.
In a 2000 study, the relationship between CYP1B1 enzyme, regular smoking, and PAH-DNA adduct formation was examined. The CYP1B1 enzyme metabolizes PAHs. The study reported that people who smoked had more risk for increased PAH-DNA adduct formation and hence had higher chances of developing lung and other types of cancers.
According to certain studies, over-exposure to UV-B rays encourages the excess production of the CYP1B1 enzyme. This is one of the top causes of non-melanoma skin cancers.
Genetic testing can tell you if you are at a higher risk for excess production of CYP1B1 enzyme in the body. If so, you may be asked to get yourself screened for different types of cancers. Genetic testing will help diagnose cancers and other health conditions because of CYP1B1 gene mutations early and improve the success rate of treatments.
The CYP2C19 gene is a member of the cytochrome P450 family responsible for the detoxification of drugs and toxins from the body.
The CYP2C19 gene is primarily found in the liver and provides instructions for the production of the enzyme that participates in the metabolism of at least 10% of commonly prescribed medications.
An important substrate that the CYP2C19 acts upon is Clopidogrel, an antiplatelet drug. Abnormal changes in the CYP2C19 gene contribute to clopidogrel resistance by affecting enzyme activity. In such individuals, the drug is less effective than in people with the normally functioning enzyme.
Considerable differences exist in the efficiency and amount of CYP2C19 enzyme produced across individuals. Depending on this, they are categorized into one of the four metabolizer statuses:
As the name goes, these individuals have higher than normal levels of the CYP2C19 enzyme. It occurs when a person has one or two copies of a form (variant) of the CYP2C19 gene called CYP2C19*17.
<5% of Asians carry this variant.
These individuals are resistant to proton pump inhibitors (PPI) therapy. PPIs are used to treat Gastroesophageal Reflux Disease (GERD), gastric or duodenal ulcer, H.Pylori infection, and NSAID damage.
Individuals having at least one copy of CYP2C19*1 are considered to be extensive or normal metabolizers. They have normal levels of the CYP2C19 enzyme.
The variants CYP2C19*2 and CYP2C*3 results in loss of function of the gene and cause low enzyme activity. They are called null variants. Individuals having these variants are called poor metabolizers.
Around 10% of people are poor metabolizers, and the antiplatelet drug Clopidogrel has little or no effect on these people. So, alternate antiplatelet drugs are prescribed to them.
Blood levels of the drug amitriptyline ( a cyclic antidepressant) are found to be high in poor metabolizers. A lower starting dose may benefit these individuals.
Similarly, the blood levels of voriconazole (an antifungal drug) are found to be high in these individuals, and treatment using this drug usually begins with lower doses.
The CYP2C19 gene acts upon many prescribed drugs and medications. Common substrates of this gene include:
While some substrates induce (or increase) the activity of the gene, some substances reduce it.
Studies have shown a reduced activity of the CYP2C19 gene in women who take oral contraceptives. This is said to occur because the metabolic product of the oral contraceptive reduces the CYP2C19 function.
The CYP2C19 enzyme helps to convert arachidonic acid (a healthy omega-6 fatty acid that is beneficial for health, especially in infants) into Epoxyeicosatrienoic acids (EETs). These EETs have a beneficial and protective effect on the heart and blood vessels.
A study reported that reduced activity of the CYP2C19 enzyme is associated with heart disease.
Higher activity of the CYP2C19 gene has been associated with depression. Also, low CYP2C19 activity has been associated with a lower prevalence of major depressive disorder and depression symptoms.
Inducers are substances that increase the activity of an enzyme whereas inhibitors are substances that bind to an enzyme to reduce its activity.
There are over 30 known variants (or types) of the CYP2C19 gene.
|CYP2C19*2||Inactive (Non functional variant)|
|CYP2C19*3||Inactive (Non functional variant)|
|CYP2C19*4||Inactive (Non functional variant)|
|CYP2C19*5||Inactive (Non functional variant)|
|CYP2C19*6||Inactive (Non functional variant)|
|CYP2C19*7||Inactive (Non functional variant)|
|CYP2C19*8||Decreased enzyme activity|
|CYP2C19*17||Decreased enzyme activity|
|CYP2C19*27||Decreased enzyme activity|
A haplotype is a group of gene changes that are inherited together. The *3, *4, *17, *27, etc., are star alleles. Star alleles are used to name different haplotypes.
The commonly studied variants are CYP2C19 *2, *3, and *17.
This is the most common type seen in the Caucasian population. This type reduces the activity of the CYP2C19 gene, reduces the metabolism of certain drugs, and increases the risk of cardiovascular diseases.
The presence of this type of gene reduces the metabolism of commonly prescribed drugs in individuals.
Individuals who are carriers of this variant of the CYP2C19 gene show aggravated response to Clopidogrel and have an increased risk of bleeding.
Recommendations For Optimum CYP2C19 Activity
Individuals with excessive or reduced activity of the CYP2C19 gene are advised against making significant changes to their diet, lifestyle, or taking supplements with their healthcare provider.
Genetic testing is recommended for individuals who need to be prescribed medications that the CYP2C19 gene acts on to determine the right alternative and the appropriate dosage.
Sulfation is a process where sulfate molecules are added to different endogenous (produced internally in the body) and exogenous (consumed from outside) substances. Sulfation is one of the essential processes of Phase 2 detoxification.
Sulfation happens with the help of the Sulfotransferase enzymes (SULTs). This reaction was first identified in 1876 when a scientist detected phenyl sulfate in the urine of a person who consumed phenol.
The SULTs transfer sulfonate (SO3 –) from the 3‘–phosphoadenosine 5‘–phosphosulfate (PAPS) coenzyme and add them to the hydroxyl or amino group elements that need to be detoxified.
There are two groups of SULT enzymes.
Membrane-bound SULTs - They primarily help metabolize endogenous hormones, neurotransmitters, peptides, and lipids. The enzymes are present in the Golgi apparatus (a subunit within the cells)
Cytosolic SULTs - These are present in the cytosol (a liquid component found inside cells) and help regulate endogenous and exogenous substances.
Sulfation helps in clearing many phenolic drugs (drugs derived from plants), hormones, neurotransmitters, and environmental toxins.
SULTs metabolize the following endogenous substances.
SULTs also play a role in converting major procarcinogens (cancer-causing agents) into their more active form before the body eliminates them.
Most of the detoxifying enzymes are expressed only in adulthood and are not found in early life. SULTs are different in that way. Studies show that SULTs may help in detoxification in the liver of fetuses as early as 20 weeks of pregnancy).
In some cases, adding a sulfate molecule to another molecule makes it more water-soluble and is then quickly eliminated from the body.
There are three kinds of SULT families identified in human beings: SULT1, SULT2, and SULT4. All these, together, produce about 13 different enzymes.
The SULT1A1 enzyme is one of the essential sulfotransferase enzymes and is expressed majorly in the human liver. It is also found in other places like the brain, intestine, platelets, kidneys, and lungs.
SULT1A1 enzyme converts a lot of cancer-causing agents into their more active intermediate forms. These intermediates can cause gene changes (mutations) and an increased risk of cancer.
A 2004 study explored the effects of SULT1A1 gene changes and the risk of breast cancer in Chinese women. The study reports a positive relationship between SULT1A1 gene variations, changes in the SULT1A1 enzyme levels, and breast cancer.
Another meta-analysis analyzed the reports of 20 individual case-control studies that related SULT1A1 gene changes to the risk of breast cancer. This study concluded that the SULT1A1 Arg213His gene variation (genetic polymorphism) can increase the risk of breast cancer, especially in the Asian population.
The C allele homogenous of the SNP rs1042157 of the SULT1A1 gene leads to slow sulfation of phenolic substances and drugs.
The below are substances that get sulfonated in the body.
Genetic testing can help understand SULT activity in the body. Some people with changes in the SULT genes may need to get screened for cancers more frequently.
Certain kinds of foods and ingredients induce or inhibit SULT activity in the body.
Substances that induce SULT:
Substances that contain dietary sulfur and can boost sulfation:
Below is the list of foods and substances that can inhibit sulfation activity. If your SULT enzymes are underactive genetically, then you should restrict or avoid these.
Phase 3 of detoxification is the final step of the detoxification process in the body and involves the elimination of the toxins from the body. As this phase is actively involved in transporting waste out of the cells and eventually the body, this phase of detoxification is called the antiporter phase.
Phase 3 is performed by transporting proteins that help move the processed toxins to urine via the kidneys or feces via the intestines.
Elimination is the end goal of phase 3 of detoxification. Some lifestyle factors that lead to poor elimination of waste from the body include:
The enzymes that regulate phase 3 of the detoxification process allow toxins to move across cellular barriers in the liver, gastrointestinal system, kidneys, and the blood-brain barrier.
The p-Glycoprotein family of proteins is an important antiporter found in the small intestine. They enable toxins to move from the cells into the gut. The blood-brain protein is another protein found in the kidneys, liver, and the blood-brain barrier and regulates phase 3 of detoxification.
Two groups of proteins primarily involved in phase 3 of the detoxification process include the ATP-Binding Cassette Transporters (ABCs) and Solute Carriers (SLC10s). SLC10A1 and SLC10A2 play an important role in phase 3 of detoxification by participating in the production, absorption, and excretion of bile salts.
The ABCB1 gene is also called the MultiDrug Resistance 1 (MDR1) or the P-Glycoprotein (P-GP). It gives instructions to produce an important ATP-dependent Phase 3 antiporter protein responsible for transporting various xenobiotics, drugs, lipids, and other exogenous and endogenous toxins out of cells for excretion.
Solute Carrier proteins are responsible for transporting solutes, including toxins, across the cell membranes, for elimination. While most SLC10 proteins are responsible for transporting bile acids, steroidal hormones, drugs, and other products, a few members of this family do not participate in the transport of bile acids.
Secretion and proper flow of bile are important for an effective detoxification process. Bile helps remove endogenous and exogenous toxins from the intestines. Impaired bile flow can result in a build-up of toxins in the body. Some substances that are eliminated through bile are:
Bile also performs other functions that are important for phase 3 detoxification.
Impaired bile flow can result in a build-up of toxins in the body, leading to diseases. Here are some ways to improve bile flow:
An important part of the detoxification process, especially phase 3, is the elimination of toxic metals. There are 23 heavy metals that are harmful to human health – antimony, arsenic, bismuth, cadmium, cerium, chromium, cobalt, copper, gallium, gold, iron, lead, manganese, mercury, nickel, platinum, silver, tellurium, tin, thallium, uranium, vanadium, and zinc (in excess). Occupational exposure and rising pollution levels in residential areas are major contributors to metal toxicity.
These heavy metals increase the production of free radicals that cause oxidative stresses in the cells of the specific organs. When the cells in these organs are overwhelmed by oxidative stress, they begin to function abnormally and cause diseases.
Fasting allows the body to rest, break down food better, and function efficiently. In the short term, fasting helps to increase the metabolic rate. Fasting also helps toxin removal from the cells more efficiently by releasing certain enzymes involved in the detoxification process.
Exercise alone cannot detoxify the body, but along with a healthy lifestyle, it enhances the functioning of various organs like the liver, kidneys, lungs, immune system, and intestines to improve detoxification. A study conducted in Sweden reported that exercising releases the various stored toxins from the cells into the blood, making it easy to eliminate them.
1. Phase 3 of detoxification is the final step of detoxification and aims to eliminate the toxins from the body.
2. This phase is regulated by a few groups of enzymes, primarily the p-Glycoprotein family of proteins.
3. ABCB1, SLC10A1, and SLC10A2 genes have an important role to play in regulating phase 3 of detoxification.
4. Bile production and flow are vital for an effective detoxification process as it eliminates bilirubin, metals and maintains cholesterol balance in the body.
5. Phase 3 of detoxification is also vital for preventing metal toxicity.
6. We can maintain healthy detoxification by following a healthy lifestyle, avoiding toxic foods and toxins in the environment, fasting, and regular exercising.
The phase 1 detoxification process transforms toxins, drugs, and other harmful substances in the body into active forms. The active forms are more toxic and have to be quickly removed to avoid damage to the body.
This is done by phase 2 detoxification. This phase is called the conjugation phase. Conjugation is the process of joining two things together. In phase 2 detoxification, the active compounds from phase 1 are modified to lower the toxicity and make them water-soluble for easy elimination from the body.
The phase 2 detoxification stage is very important in protecting the cells from cancer-causing chemicals (carcinogens).
There are six different pathways in phase 2 detoxification that are aided by different enzymes. All these pathways need to work harmoniously for efficient detoxification. The conjugated products are sent to phase 3 detoxification and are finally eliminated.
Glutathione conjugation is a pathway that uses glutathione to neutralize toxins. Glutathione is a type of antioxidant that helps prevent cell damage and oxidative stress. The Glutathione S-transferases (GSTs) are a group of enzymes that help combine glutathione with active toxin elements.
The conjugation makes the toxins water-soluble and makes it easy to remove them from the body.
GSTs helps detoxify the following:
GSTs are distributed throughout the body in the liver, kidneys, brain, spleen, intestines, lungs, and skeletal muscles.
Proteins: Amino acids are the bases of glutathiones. Lowered levels of protein intake may alter amino acid levels in the body and lead to reduced ability to produce glutathione.
Omega-3 fatty acids: Inflammation in the body reduces glutathione supply. Omega-3 fatty acids can help reduce chronic inflammation. Include omega-3 rich foods like fatty fish, nuts and seeds, avocados, and fish oil in your food.
Amino acids are building blocks of proteins. Some of the amino acids can attach themselves to toxins and make them water-soluble and easy for excretion.
Two enzymes help with amino acid conjugation - Acyl-CoA synthetases and Acyl-CoA amino acid N-acyltransferases.
A common amino acid - glycine, helps in removing toxic benzoate from the body. Benzoate is a very common preservative used in foods.
Protein: Food sources like meat, seafood, poultry, eggs, and dairy products are rich sources of proteins. They help improve amino acid levels in the body.
Amino acid supplements: Amino acid supplements are a mix of essential amino acids in the right quantities and help improve amino acid levels in the body.
Methylation is the process of substituting one atom in a substance by a methyl group. In this pathway, a methyl group is added to toxins to make them biologically less active to help transport them out. This pathway uses the Methyltransferases (MT) enzyme group for conjugation.
There are many MT enzymes, but the most important ones are the Thiopurine S-methyltransferase (TPMT) and the Catechol-O-methyltransferase (COMT).
TPMT helps in the methylation of heterocyclic sulfhydryl compounds like thiopurines (immunosuppressive drugs).
COMT helps in the methylation of neurotransmitters like dopamine, epinephrine, and norepinephrine. There are two forms of COMT. The membrane-bound catechol-O-methyltransferase (MB-COMT) is produced by the brain's nerve cells. The shorter version called the soluble catechol-O-methyltransferase (S-COMT) helps send out excess hormones in the body.
Folate: Folate is a methyl donor and helps make methyltransferases (MT). Foods like legumes, dark leafy greens, beetroots, and cruciferous vegetables are rich in folate.
Choline: Choline is an essential nutrient that acts as a methyl donor and helps in the methylation process. Foods like red meat, eggs, seafood, whole grains, legumes, and dairy products are choline-rich.
Vitamins B2, B6, and B12: - These three vitamins play a role in methyl metabolism and help act as methyl donors. Foods like dairy, liver and kidney, shellfish, dark green vegetables, and red meat are rich sources of B vitamins.
Sulfonation is the process of attaching sulfates to toxins to neutralize them. In sulfonation, sulfotransferase enzymes (SULTs) transform various steroids, peptides, vitamin D, serotonin, and catecholamines (neurotransmitters) in the body. SULTs also help remove the following toxins from the body.
Retinoic acid (Vitamin A): Vitamin A can induce (promote the production of) SULT enzyme in the body. Food sources like liver, fish, eggs, dairy products, fruits, and vegetables like apples, asparagus, and carrots are rich in vitamin A.
Caffeine: Certain studies show that caffeine sources like coffee, tea, green tea, and cocoa can increase SULT activity.
In acetylation, the N-terminal acetyltransferases (NATs) enzymes make use of acetyl CoA to attach themselves to the toxins. NATs are responsible for removing different types of carcinogens (cancer-causing agents) present in food and the environment. These also are responsible for removing excess folate from the body.
There are two NAT enzymes - NAT1 and NAT2 that are important parts of acetylation.
Quercetin: Quercetin is a natural flavonoid found in various fruits and vegetables like cherry tomatoes, broccoli, blueberries, kale, and apples. A small study found that consuming 500 mg of quercetin a day helps improve NAT enzyme levels.
The glucuronidation pathway is the most important one of phase 2 detoxification. This pathway uses the help of the UDP-glucuronosyltransferases (UGTs) enzymes.
UGTs help in the elimination of the following toxins and hormones.
- Cruciferous vegetables: Cruciferous vegetables like cabbage, cauliflower, Brussel sprouts, and broccoli help increase UGT enzymes
- Lycopene: Lycopene is a type of carotenoid that has antioxidant properties. It helps increase UGT enzymes. Some sources of lycopene include pink and red-colored fruits and vegetables like watermelons, pink grapefruits, and tomatoes.
- Ellagic acid: Ellagic acid is a type of natural antioxidant that increases UGT enzymes. Foods like pomegranate, berries, blackcurrants, and walnuts are rich sources of ellagic acid.
- Ferulic acid: Ferulic acid is another antioxidant that increases UGT enzymes. Foods like broccoli, carrots, parsnip, olives, berries, and roasted coffee are rich in ferulic acid.
1. The phase 2 detoxification stage is called the conjugation phase. The toxins transformed in phase 1 are made "less dangerous" to the body in phase 2.
2.There are six pathways in this phase 2 detoxification. - Glutathione Conjugation, Amino Acid Conjugation, Methylation, Sulfonation, Acetylation, and Glucuronidation.
3. The glutathione conjugation pathway makes use of Glutathione S-transferase (GSTs) enzymes to make toxins water-soluble and less active.
4. The amino acid conjugation pathway makes use of amino acids to combine with toxins and makes them easier to send out of the body.
5. The Methylation pathway adds a methyl group to the toxins and makes them biologically less active.
6. The Sulfonation pathway attaches sulfates to toxins to neutralize them.
7. In the Acetylation pathway, the N-terminal acetyltransferases (NATs) enzymes are used to remove different carcinogens that enter the body through food.
8. The glucuronidation pathway is one of the most important phase 2 detoxification pathways. This uses UDP-glucuronosyltransferases (UGTs) enzymes to remove a wide range of toxins from the body.