CYP2C19 – Metabolizing medications

The CYP2C19 enzyme is responsible for the breakdown of several popular drugs including proton pump inhibitors (Prilosec, Nexium, Prevacid), certain anti-epileptics, and an antiplatelet drug (Plavix).  CYP2C19 is also involved in activating and breaking down some hormones such as progesterone.

There are variants of the CYP2C19 gene that cause some people to be poor metabolizers and others to be fast metabolizers. You can have increased side effects (depending on the medication) either from being a slow metabolizer or a fast metabolizer.   For example, a fast metabolizer taking omeprazole to treat h. pylori may have an insufficient response due to the drug not remaining active in the body long enough.[ref]  Alternatively, some drugs such as Plavix are converted into their active drug state through CYP2C19, and being a poor metabolizer could mean that Plavix (an anticoagulant) isn’t activated quickly enough. [ref]

Valium (diazepam) is another common drug metabolized in part by CYP2C19 (along with CYP3A4). Currently, there are no official recommendations to physicians as to reducing the dosages for poor metabolizers, but there is a box warning about CYP2C19. [ref]

A couple of SSRI’s, Celexa (citalopram), Zoloft (sertraline) and Lexapro (escitalopram), are also metabolized mainly through CYP2C19.[ref]

Approximately 10 – 20% of Asians are poor metabolizers, as are 2 – 5% of people of Caucasian descent.  Up to 20-30% of Caucasians are fast metabolizers, but less than 5% of Asians are.  So there is a wide variation on how drugs are metabolized by this gene.

Here is a complete list of drugs metabolized by CYP2C19.

Beyond Drug Metabolism:
So for a person not on any drugs, what does the CYP2C19 gene do?  Obviously, we don’t have a gene just waiting around for us to take a valium.  It is involved (minor) in metabolizing melatonin[ref] and is also involved in the metabolism of estradiol.[ref]

Poor metabolizers:  

Check your 23andMe results for rs4244285 (v4, v5):

  •  AA:  non-functioning (CYP2C19*2)
  •  AG: poorer metabolizer
  •  GG:  Normal    [ref]


Check your 23andMe results for rs4986893 (v4, v5):

  •  AA: poor metabolizer (CYP2C19*3), increased risk of lung cancer[ref]
  •  AG: slow metabolizer
  •  GG:  Normal    [ref]

Ultra-fast metabolizers:

Check your 23andMe results for rs12248560 (v4, v5):

  •  CC: normal
  •  CT: ultrafast metabolizer (CYP2C19*17), more likely to benefit from tamoxifen treatment
  •  TT: ultrafast metabolizer (CYP2C19*17), more likely to benefit from tamoxifen treatment [ref]



Don’t smoke:  If you are a CYP2C19 poor metabolizer and a smoker, you are at a 5x increased risk of lung cancer[ref] and a 17x increased risk of laryngeal cancer.[ref]

Interactions with natural substances:

  • D-limonene, a component of citrus essential oils, is also metabolized through CYP2C19.  If you are a poor metabolizer and taking a medication metabolized through CYP2C19, you may not want to take supplements or essential oils with d-limonene at the same time as the medication.
  • Inhibitors of CYP2C19 may also interfere with medications that you are taking.  Common supplements such as quercetin, berberine, and caffeic acid.[ref][ref]
  • Inducers of CYP2C19 include low-dose aspirin.[ref]

Read more: This is part of an ongoing series of posts about the CYP450 enzymes and detoxification.


Liver Detox Genes: CYP2C9 Genotypes and Drug Metabolism

Have you ever wondered why certain medications don’t work well for you? Genetic variants can change how fast or how slow the medication is broken down in your body.

CYP2C9 is a gene that codes for an enzyme that metabolizes quite a few medications in the liver as well as linoleic acid, arachidonic acid, and serotonin outside of the liver.[ref]

Some of the most prescribed drugs metabolized with CYP2C9 include losartan (blood pressure), Warfarin, acenocoumarol, tolbutamide (Orinase), glipizide (Glucotrol), ibuprofen (Advil, Motrin), celecoxib (Celebrex), montelukast (Singulair), naproxen (Aleve).  A complete list can be found on Pharmacy Times.

There are several genetic variants of CYP2C9  that either increase or decrease the activity level of the enzyme.

This is important when looking at how your body is going to respond to different doses of common drugs.  For example, with some loss-of-function variants of CYP2C9, people may have an increased risk of stomach bleeding with NSAIDs.[ref]  Celecoxib is another drug that is metabolized by the CYP2C9 enzyme, and a new study recommends a lower starting dosage for those with reduced enzyme function.

Warfarin is a popular prescription anticoagulant, often used after strokes or for those at risk for blood clots.  Dosage variations that are determined by genetic factors are mainly based on the CYP2C9 and VKORC1 gene variants.

A popularly prescribed statin, Crestor (rosuvastatin), is also partially metabolized by CYP2C9.  A recent study found that those with slow CYP2C9 variants had more of a reduction of LDL levels when using rosuvastatin.

THC, the active component of marijuana, is partially metabolized by CYP2C9. [ref]

CYP2C9 Genetic Variants

While more than 50 variants of CYP2C9 have been found, a few of the more common variants that are available in 23andMe raw data are listed below.

Check your 23andMe results for rs1799853 (v4, v5):

  •  TT: CYP2C9*2 – poor metabolizer; 40% reduction in Warfarin metabolism [study]
  • CT:  One copy of CYP2C9*2, reduced activity
  •  CC: normal


Check your 23andMe results for rs1057910 (v4, v5):

  • CC: CYP2C9*3 – poor metabolizer; 80% reduction in Warfarin metabolism [study]
  • AC:  One copy of CYP2C9*3, reduced activity; 40% reduction in Warfarin metabolism
  •  AA: normal


Check your 23andMe results for rs2256871 (v4, v5):

  • GG: CYP2C9*9 – poor metabolizer [ref][ref]
  • AG:  One copy of CYP2C9*9, decreased metabolism
  •  AA: normal


Check your 23andMe results for rs9332131 (v4, v5):

  •  – – or DD: CYP2C9*6 – poor metabolizer[ref]
  • II: normal


Check your 23andMe results for rs28371685 (v4, v5):

  • TT: CYP2C9*11 – poor metabolizer [study]
  • CT: One CYP2C9*11 allele, reduced activity
  • CC: normal


Short-term fasting may reduce CYP2C9 activity; a 36 hour fast reduced CYP2C9 activity by 19%.  Keep this in mind if you are taking a medication that is metabolized by CYP2C9 as this can affect how long the medication is active for you.  For example, this could affect your clot time if you are taking Warfarin while fasting.

Hesperitin, a flavonoid found in lemons and oranges, is an inhibitor of CYP2C9.[ref]

Quercetin interacts with warfarin dosages, but not through CYP2C9 metabolism.  “Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin.”

More to read:


Is the nootropic drug modafinil likely to work for you?

Modafinil is being used as a nootropic drug that increases alertness and gives a sense of well being — to some users. Like most drugs, individual results seem to vary.  One reason for the variation is a common genetic variation in the COMT gene.

Modafinil is a prescription medication (in the US) for decreasing daytime drowsiness in narcolepsy patients.  Off-label, it is a popular drug for neuroenhancement. Does it work? Clinical trials have shown that it is effective for cognitive enhancement, but the trials didn’t differentiate between genotypes and show a range of effectiveness.

Modafinil is thought to work by increasing dopaminergic neurotransmission, which depends on the activity of the gene, COMT (catechol-O-methyltransferase).  COMT is the enzyme that breaks down neurotransmitters (including dopamine, epinephrine, and norepinephrine), and the rate at which it metabolizes the neurotransmitters affects their levels in the brain.

When investigating modafinil’s effectiveness in people with different genotypes, research results showed that those with the COMT Val/Val genotype had a much better response than those with the Met/Met genotype in terms of sustained vigilant attention. In fact, the study says that modafinil “was hardly effective in subjects with the Met/Met genotype”. For both genotypes, modafinil worked in keeping the subjects from feeling sleepy, so the difference in genotype was on the cognitive benefits rather than wakefulness.

Check your 23andMe results for rs4680 (v.4 and v.5):

  • GG: (Val/Val) higher COMT activity, better response to modafinil
  • AG: intermediate COMT activity
  • AA: (Met/Met) lower COMT activity, not as much response to modafinil


Another study looked at the effects of modafinil on REM and non-REM sleep and found that it varied by COMT genotype. This sleep deprivation study found that modafinil increased specific EEG activity in those with the Val/Val genotype during sleep recovery (after modafinil and sleep deprivation for 40 hours).  The study concludes: ” in NREM sleep, the drug increased EEG activity in 3.0-6.75 and > 16.75 Hz frequencies exclusively in Val/Val allele carriers. Taken together, the data show that the promotion of wakefulness by pharmacological interference with dopaminergic and adenosinergic mechanisms differently affects sleep EEG markers of sleep homeostasis.”


If you’ve ever tried modafinil and wonder why it didn’t have much of an effect on you, perhaps the reason is in your genes.

I’m not going to weigh in on whether or not you should take modafinil… or where to buy it. You can go read about it on Reddit for that type of info.

If you have histamine intolerance, mast cell problems, or anorexia, please note that modafinil may increase histamine levels in the brain.

If you are interested in other effects of the COMT gene, check out my article: COMT – Genetic Connections to Neurotransmitter Levels

If you are wondering about the metabolism of other drugs, I suggest starting with checking your phase I detoxification genes (CYP450’s) through my  Phase I Detox report or by reading about it here.


Why Allegra may not work as well for you: genetics of ABCB1 proteins (Patrons only)

Ever wonder why a certain medication may work great for a friend and do nothing for you?  One reason could be your genes.

Let’s take fexofenadine (Allegra) for example.  You have watery eyes and a drippy nose during spring allergy season and pop an Allegra.  There is a lot that goes on in your body before that medication brings about allergy relief.  It has to dissolve, be absorbed, get transported to the cells where it is going to act — and it has to stay inside of those target cells.

Staying inside the cells instead of the medicine being transported back out again is where genetics comes in to play.

Some medications and other toxins are transported back out of cells by an ATP-binding cassette transporter protein encoded by the ABCB1 gene.  In the epithelial cells that line your intestines, the ABCB1 proteins are involved in pumping substances back into the intestinal lumen.  So imagine if you take an Allegra, it dissolves, gets absorbed, and then part of that gets pumped back into the intestines to be eliminated. Genetic variants in ABCB1 affect how much stays in the cells vs getting eliminated (through intestines, bile, urine).

In general, it seems like a good thing for the body to get rid of a substance that it thinks might be toxic. While an allergy medication not working quite as well is not that big of a deal, the real problem comes in when trying to keep chemotherapy drugs inside of cancer cells in order to act upon them.  This gene has been studied in depth for cancer treatment drugs.

ABCB1 gene (multidrug resistance protein, p-glycoprotein):

This rest of this article is available for patrons through Patreon.


Detoxifying Phthalates:  Genes and Diet

PhthalateGeneticsThere have been several recent studies about phthalates that have piqued my interest. I decided it was time to look into the science behind the stories and see if there really is anything to the scare-tactic type headlines about phthalates. Below are my notes with links to studies. I encourage you to check out the research and come to your own conclusions about whether phthalates are something to worry about for your body — and whether there is really anything you can do…

What are phthalates?
Phthalates are a type of chemical used as plasticizers to make plastics more pliable. They are not bonded to the plastic, thus allowing them to come out of plastic products when exposed to heat or solvents. “Because they are not covalently bound into plastic when used as plasticizers, phthalates have been found to leach or migrate from PVC-containing items into air, dust, water, soils, and sediment ” [study]

Phthalates are commonly found in adhesives, caulk, vinyl products, flooring, coatings on pharmaceuticals, flexible coatings on extension cords and appliance cords, nail polish, food and other packaging, fragrances, personal care products, paints, carpet backing, faux leather, printing inks, and apparently in mac and cheese.  Several types of phthalates are banned in the US and the EU now for use in toys and other objects, such as teething rings, that can fit in a child’s mouth.

In addition to food containing phthalates due to processing or packaging, prescription and over the counter medicines (2012) can contain phthalates as excipients. [study]  In 2010 the FDA created a list of products that they had tested for phthalates – fragrances were a huge source of phthalates of the products they tested.

Are phthalates really a problem?
I guess to answer that question, you would have to define ‘problem’.  Phthalate exposure is probably not going to kill you outright. They are not a new substance, and there have been quite a few toxicity tests dating back to the 1970’s using rats as a model.  US government toxicology studies in 1995 on rats showed that it didn’t kill adult rats in 13 weeks, but the doses used did kill baby rats.

There is some question, though, as to whether rodent studies are good models for human metabolism of phthalates, and newer studies now indicated that rats do not metabolize phthalates the same way that humans do.  [study] Exposure limits based on mouse studies are set fairly high, at around 100 mg/kg/day, as far as tumorigenesis. But California does include 6 types of phthalates on their list of possible carcinogens in their Prop 65 regulations.

Even though they probably aren’t going to kill you and probably won’t give you cancer, some of the harms of phthalates have been clearly shown, especially with infant and child exposures. Some types of phthalates have been removed over the past 15 years or so from teething rings and bottle nipples (EU and FDA regulations) and in 2009 US banned certain phthalates from use in children’s toys.

Some of the evidence showing that phthalates do have an effect on people and animals in low, chronic doses includes:

  1. Phthalates act as an endocrine disruptor
  2. As an endocrine disruptor, phthalates may increase the risk of fibroids, obesity, asthma, ADHD, IVF problems, and reproductive problems in men.
  3. It may be leading to a global decrease in amphibians – phthalates at very, very low, chronic levels are affecting frogs’ sperm.

So if low, chronic doses of phthalates are a problem, where are they coming from?
It turns out that phthalates are ubiquitous – literally everywhere – in our food supply.  For example, 2014 Norwegian study found phthalates in all foods and beverages commonly consumed (and BPA in 54%).  Exposure was highest in meat and grains, but levels were on average less than European max exposure levels.  Phthalates are even a problem for those trying to eat clean, organic food which is stored in glass. A study found that levels in junk food were the same as for those eating a controlled organic diet with food stored in glass containers instead of plastic.

How do phthalates get into our body?
One study sums up the routes of exposure well: “According to a review by Cao, phthalates can migrate into food from plasticized PVC materials such as tubing typically used in the milking process, lid gaskets, food-packaging films, gloves used in the preparation of foods, and conveyor belts [19,20]. These compounds are also found in printing inks and adhesives on food wrappers as well as coatings on cookware that have been contaminated by packaging [20-22]. Foods high in fat are contaminated by higher weight phthalates that are more lipophilic such as DEHP [19].”

Another study notes: “In the United States, phthalates have been approved by the Food and Drug Administration (FDA) as plasticizers in food packaging materials and food contact substances used during processing and storage while the European Commission and Chinese authorities have limited phthalates in food contact materials made of plastic since 2008–2009”

Finally, if you aren’t eating or breathing phthalates, they may be in medications that you take.  Some pharmaceuticals also use phthalates as plasticizers their drug capsules or coatings; even if not deliberately added to drugs, a recent study in China found phthalates at varying levels in all medications that they tested.

phthalate-linkedWhat are the effects of phthalates on the body?
Below are just some of the studies that show different effects of phthalates.  This is not a comprehensive list, so I hope you will do some researching on your own if you are interested in other effects of phthalates.  As with most environmental factors, it is likely that phthalates affect different people in different ways based on their genetic susceptibility.

  • ADHD “Consistent with previous studies [18], we found a significant correlation between the urine phthalate metabolite concentrations and the poor attentional performance” [study]
  • Lower odds of in vitro fertilization working for those with higher phthalate levels.  This study found that those in the top quartile for phthalate metabolites had about half the chance of IVF working.
  • Low dose, long-term study (mice) found decreased reproduction in males and decreased testosterone levels
  • The main problem with phthalates stems from their role as endocrine disruptors, which could cause problems with obesity, thyroid function, and uterine issues.
  • Obesity and weight gain:
    • Contaminated dust containing phthalates (which was found in all of the household dust sampled) was found to cause human cells to create triglycerides and also to cause mice to get fat.
    • Previous studies in cells have similar findings for phthalates promoting fat accumulation.
    • Sometimes the best way to figure out the impact of a substance on a population as a whole is to put a price on it. This is especially true in countries with government provided healthcare, and a recent European study calculated the cost of obesity caused by phthalates.   “The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and €15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with €607 million in associated costs.”
    • A March 2017 study says “Most data support the effects of bisphenol A and some phthalates … on the development obesity and type 2 diabetes mellitus.”
  • Thyroid function is also affected by phthalates:
    • Several studies link urinary phthalate levels to depressed thyroid levels.
    • A Korean study found phthalate metabolite levels to correlate to lower FT4, FT3 and just slightly higher TSH levels.
    • Rat study showing that phthalates decrease T4, T3 and TRH but not TSH
    • Most doctors prescribe thyroid medications based on TSH, so if phthalates are messing with Free T3 and Free T4 but not TSH, there could be a lot of people with lower thyroid function that are being missed by doctors.  Check out Stop the Thyroid Madness for more information on FT4, FT3, and all the other thyroid hormones.
    • Another study explains how this links to obesity: “Another possible mechanism by which phthalates might promote obesity is through the disruption of thyroid function, which plays a key role in the regulation of energy balance and metabolism. … In rodent studies, exposure to DEHP lowered plasma thyroxine and decreased iodide uptake of thyroid follicular cells26,27). Recent human studies have also demonstrated possible effects of phthalate exposure on thyroid function in children and adults”
  • Uterine fibroids:
    • There are quite a few studies linking phthalates and other endocrine disruptors to fibroids and other uterine problems. Although most of the studies seem to be small or else reliant on self-reported cases of fibroids, the studies all seem to point to the same thing – a link between endocrine disrupting phthalate metabolites and fibroids.
    • Again, putting a price on the issue may give a bigger picture to what is going on.   A 2016 study estimated the cost of endocrine disruptor caused fibroids at 1.3 billion euros in the EU.
    • The truth may lie in the fact that not everyone is affected the same way by phthalates. A study showed that women with certain CYP17A1 and ESR1 variants had both higher phthalate levels and greater risk of uterine fibroids.
  • Histamine / Mast Cell / Allergy connection:

What happens to phthalates in your body?
According to this study, phthalates are metabolized rapidly and excreted in urine and feces.  Phase I metabolism involves hydrolysis by lipases, which are enzymes produced in the pancreas and stomach.  Depending on whether the phthalates are high or low molecular weight, they can also be further metabolized the oxidation.  The oxidative metabolites can then go through glucuronidation in phase II metabolism.

So which genes are involved in breaking down and getting rid of phthalates?

  • A GSTP1 variant, rs1695 AA, is associated with increased risk of asthma with phthalate exposure
  • “Humans are mainly exposed to DEHP via ingestion of food. Once absorbed into the body, DEHP is rapidly hydrolyzed to mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (2-EH) by the catalytic action of lipase [2, 3]. A part of MEHP is further oxidized by various cytochrome P450s (CYPs), followed by alcohol dehydrogenase (ADH) or aldehyde dehydrogenase (ALDH), to produce dicarboxylic acid or ketones. The remaining MEHP is excreted in the urine directly or in the conjugation form by the catalytic action of UDP-glucuronocyltransferase (UGT). 2-EH is metabolized mainly to carboxylic acid [mainly 2-ethylhexanoic acid, 2-EHA] via 2-ethylhexanal by the catalytic action of ADH and ALDH [2]. The 2-EHA formed is further oxidized to a dicarboxylic acid in a way similar to MEHP oxidation.”
  • Phase 1 detoxification is thought to be mainly through hydrolysis by lipases. Lipases are a type of enzyme produced in the pancreas, saliva, and bile.  They are what break down the fats that you eat.
    I found one EPA report that implies that the PNLIP and LIPF genes code for the pancreatic and gastric lipases that break down phthalates, but I couldn’t find any other studies to confirm this.
  • Some phthalate metabolites also induce CYP450 genes including CYP2B6.
  • While I didn’t find any specific studies on CYP2B6 variants and phthalates, there are a couple of variants that cause impaired metabolism by CYP2B6.
  • UGT enzymes involved in the glucuronidation (phase II metabolism) of phthalates include UGT1A9, UGT1A3, UGT1A7, UGT1A10, UGT2B7  — check out my article on UGT genes
  • GSTM1 (Glutathione S-Transferase Mu 1) has been shown in several studies to interact with phthalates.  The main variant of GSTM1 is known as GSTM1 null, meaning it is absent.
    • A small study, but one that has been replicated and cited by quite a few other studies, found that for those with GSTM1 null genotypes and phthalate exposure, the risk of fibroids was about 5 times greater.
    • Check your genetic data for rs366631. (v.4) It is a proxy for GSTM1 null with the AA genotype corresponding to null.  About 50% of the population is null.

So what can you do about phthalates, especially if you genetically may not be detoxifying them well?

  • First, while avoiding plastics and not heating your food up wrapped in plastic wrap may help a bit overall, I think that studies have shown that almost all food these days contains low levels of phthalates. A lot of fragrances have phthalates in them, so removing air fresheners (or switching to essential oils) may help as well.
  • Vegans eating only organic do have slightly lower levels of phthalates.   I’m not sure that switching to an organic, vegan diet is worth it just for the slight decrease in phthalate levels.
  • High frequency of dusting does decrease phthalates in the air at home. But make sure you aren’t using a furniture polish or spray that contains phthalates.
  • While I have read mixed results before about sweating out toxins, studies do show that phthalates can be excreted in sweat, thus saunas and exercise may be a good way to get rid of phthalates.
  • If you have a GSTM1 null gene type (see above), high fruit and vegetable consumption should help out.
  • Supplementing with the antioxidants vitamin E and C may help with GSTM1 null. Especially vitamin C.
  • If you have UGT polymorphisms (and even if you don’t), one way to boost the power of these phase II enzymes is to inhibit beta-glucuronidase, an enzyme produced by gut bacteria that basically reverses the glucuronidation of toxins by UGT enzymes. Calcium D-glucarate supplements are one way to inhibit beta-glucuronidase.  Bifidobacteria longum, l. plantarum, and l. acidophilus also inhibit the bacteria that produce beta-glucuronidase.

Personal Plan of Action:
A lot of the above problems and genetic variants apply to me personally.  My personal plan of action includes:

More to read:


Phase II Detox – NATs

N-acetyltransferase is a phase II detoxification enzyme that helps to metabolize 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. Although 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 1950’s to play a role in the metabolism of tuberculosis drug. A significant percentage of people were found to be poor acetylators resulting in significant side effects of the tuberculosis drug, isoniazid.

Genetic variants involved:

NAT1 metabolizes p-aminobenzoic acid (PABA) and p-aminosalicylic acid (PAS).[ref] PABA used to be commonly found in sunscreens, and PAS is used as an antibiotic for tuberculosis. It also breaks down components of cigarette smoke and heterocyclic aromatic amines, which forms when meats and seafood are grilled at high temperatures.

There have been studies linking NAT1 genetic variants to an increased risk of bladder, colon, breast, lung, prostate, and pancreatic cancers. [ref]

Smoking is even more risky 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]

It has recently been found that NAT1 slow acetylators have more DNA adducts formed with heterocyclic aromatic amines (carcinogens from meat being cooked at high temps). [ref]  Another study also found red meat consumption for slow and intermediate acetylators to be linked to 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 -AA (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. [ref] Both of those conditions are linked to folate metabolism and the methylation cycle.

Check your 23andMe results for rs4986782:

  • AA: NAT1*14B, slow acetylator [ref]
  • AG: slow acetylator,
  • GG: normal


Check your 23andMe results for rs15561:

  • AA: reduced function [ref]
  • AC: reduced function
  • CC: normal


Check your 23andMe results for rs6586714:

  • AA: lower risk of colon cancer from cooked meat carcinogens (protective) [ref]
  • AG: lower risk of colon cancer from a cooked meat carcinogens
  • GG: wildtype/common

There are several other SNPs that are not included in 23andMe data so the above SNPs are not the complete picture for NAT1.

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 for several types of cancers.

NAT2 polymorphisms also create rapid, intermediate, and slow acetylators. Slow acetylators don’t clear out toxins as well and are at a somewhat higher risk for bladder, lung, breast, and esophageal cancers. Rapid acetylators can actually make some toxins more reactive and may be at a slightly higher risk for colon cancer.

There is an online tool from the University of Albany to determine your NAT2 phenotype.  You will need to look up your data for six different SNPs.   It asks you to put in your NAT2 alleles for the following:

NAT2 rs1208 – A, has also been found to be involved in increased insulin resistance, although, to me, the effect looked pretty small.  [ref]

NAT is also being studied in relation to bacteria which can produce it, and their relationship to drug metabolism.


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

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

Detox Genes – NQO1

This is part of an ongoing series on the genes involved in detoxification.

NAD(P)H:quinone oxidoreductase 1 (abbreviated as NQO1) uses NADH or NADPH to reduce quinones to hydroquinones.   NQO1 is involved in breaking down exogenous (outside) toxins such as benzene and some chemotherapy drugs.  Benzene, a carcinogen, is found  in gasoline fumes, laundry detergent, furniture wax, industrial uses, pesticides, and smoke.

NQO1 is also involved in cellular defense against oxidative stress, reduction of CoQ, and reduction of vitamin K.  In the reduction (chemistry meaning, think redox reaction) of Vitamin K, NQO1 is mostly involved in turning K3 into the form that is active in blood clotting and bone building[ref].

Two polymorphisms have been identified.  NQO1*2 leads to a deficiency in the enzyme, while NQO1*3 has reduced a enzyme activity which may depend on the substance.   Absence of NQO1 has recently been studied (in mice) and found to lead to gut impermeability and inflammation (leaky gut) [ref].

Check your 23andMe results for rs1131341:

  • AG: NQO1*3, decreased enzyme function depending on substance
  • GG: normal


Check your 23andMe results for rs1800566:

  • AA: NQO1*2, higher cancer risk from benzene, no NQO1 [ref]
  • AG: NQO1*1/*2, somewhat higher cancer risk from benzene, intermediate enzyme function
  • GG: normal

Researchers have found that the NQO1 enzyme can be induced by green tea extract and broccoli sprouts [ref] as well as resveratrol[ref].

From a 2002 paper in the American Journal of Clinical Nutrition:

The polymorphism results in reduced amounts of the NQO1 protein, possibly as the result of to an accelerated degradation via the ubiquitin pathway. The mutant expressed in E. coli has between 2% and 4% of the activity of the wild-type enzyme (186). The cause of both of these observations is likely to be an aberrant binding of FAD by the mutant enzyme. The Pro187→Ser mutation disturbs the structure of the central parallel β-sheet (192), resulting in a reduction in binding affinity for the FAD cofactor (193). Others found that NQO1 activity can be measured only in the presence of increased concentrations of FAD, confirming that the impairment of activity in the Pro187→Ser enzyme is due to lowered FAD affinity (Ivonne Rietjens, unpublished observations, 2001).

These data suggest that individuals with the NQO1 polymorphism might benefit from high-dose riboflavin treatment by reductions in cancer risk. Further studies should be done to verify or reject this theory.

It looks like there have been several more studies done in the past few years regarding FAD and NQO1 [ref] [ref].

More to read:

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector  – this is a very thorough overview from 2011

Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components

Induction of the phase II detoxification enzyme NQO1 in hepatocarcinoma cells by lignans from the fruit of Schisandra chinensis through nuclear accumulation of Nrf2.

NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: A HuGE review


Phase II detox – GSTs

This is part of an ongoing series on the genes involved in detoxification.

Another phase II detox reaction occurs with the glutathione S-transferases enzymes, which has eight classes identified: alpha, kappa, mu, omega, pi, sigma, theta, and zeta.  The classes are abbreviated with their first letter (i.e. GSTMA for alpha).  These phase II enzymes add a glutathione to toxins in order to detoxify them.  GSTs are found in the liver, intestines, and several other places in the body and are responsible for detoxifying a large number of pesticides, herbicides, carcinogens, and chemotherapy drugs.

Once a toxic substance has been conjugated with glutathione via the GST specific enzyme, it can be excreted from the body via bile or urine.  Glutathione is considered the master antioxidant for the body.  Here is a nice article on ways to boost your glutathione level with food.

There are several fairly common polymorphisms that can decrease the function of your GSTs.  But, once again, environmental factors also play a huge role in your detox system.  So if you have non-functioning genes for a specific enzyme, your body has alternate ways to detox most substances and you can naturally boost those routes through nutrition.  One way of inducing GSTs is thought to be through cruciferous vegetable consumption.  [ref]

There have been quite a few studies done on the GST polymorphisms.  So if you find that you have one of these common polymorphisms, you may want to read up on some of the studies in PubMed.  Some studies are contradictory, and some seem to be specific to gender or ethnicity.

GSTA1 has a common polymorphism that significantly reduces its function.  When looking at research studies, GSTA1*A is the functioning enzyme, and GSTA1*B is the reduced function version.  A couple of studies show that with GSTA1*B there is a higher risk for colon cancer with high cruciferous vegetable intake, especially broccoli [ref], [ref].  Before you stop eating broccoli all together, weigh this against cancers that are prevented by it.  GSTA1*B with higher cruciferous veggie consumption were found to have more protection against breast cancer.[ref]  GSTA1*B is also associated with a higher risk of asthma and allergies. [ref]

Check your 23andMe results for rs3957357:

  • AA: GSTA1*B, low/ non-functioning enzyme
  • AG: GSTA1*A/*B
  • GG: GSTA1*A


GSTM1 has a very common (about half of some populations) mutation that is associated with little or no GSTM1 expression.  It can be found in 23andMe data through looking at rs366631 which is a SNP that has been correlated with a deletion in GSTM1.  [ref]  There are over 2500 PubMed entries for ‘GSTM1 polymorphism’, and it has been studied in reference to many different types of cancer, glaucoma, and diabetes. There is a higher risk of some cancers with non-functioning GSTM1 gene, but the association is modified for some by diet and environment.  This seems to be a mutation that should encourage people to eat healthy and not smoke!

Check your 23andMe results for rs366631:

  • AA: GSTM1, low/ non-functioning enzyme
  • AG: GSTM1 functioning
  • GG: GSTM1 functioning


GSTP1 is another GST gene with very common polymorphisms.  It is involved in estrogen metabolism, and in a 2009 US study, the polymorphism (GG) was found to reduce the risk of breast cancer in post-menopausal women vs. AA [ref]. Conversely, women with GSTP1 GG were found to have a higher risk of breast cancer in a 2008 Chinese study.  Those with the lowest intake of cruciferous vegetables with GG were found to have the highest risk of breast cancer.  [ref]  The difference between the two studies may be ethnicity or pre- vs. post-menopausal women.

A 2012 study on men taking Vitamin E (alpha-tocopherol) supplements found that those with GSTP1 AA and AG had higher levels of inflammation (measured IL-6), while those with GG had decreased IL-6 levels. It is an interesting study that is worth reading.  Note though that there were only 160 participates, male only.[ref]

A study in rats in 2015 found that carnosic acid (found in rosemary) up-regulates the GSTP enzyme.  [ref] And a study in mice found that GSTP-null mice had less weight gain on a high fat diet. [ref] Another study in mice showed less acetaminophen toxicity in GSTP-null. [ref]

Check your 23andMe results for rs1695:

  • AA: normal
  • AG: somewhat reduced GSTP1 activity
  • GG: somewhat reduced GSTP1 activity [ref]


GSTT1 is another GST with deletion or null activity being fairly common — ~20% of Caucasians and 80% of Asians.  GSTT1 null has been implicated in increased risk of several diseases: MS [ref], kidney disease from exposure to organochlorine pesticides [ref],  esophageal cancer [ref], lymphoma due to polycyclic aromatic hydrocarbons [ref], and many more.

There is no SNP that defines GSTT1 null vs present, as far as I can find.  The Genetic Genie detox report does include it.  If you go to your raw data on 23andMe and search for the GSTT1 gene, a lot of ‘no call’s should indicate GSTT1 null.


Liver Detox Genes – CYP3A

This is part of an ongoing series on the genes involved in detoxification.

The CYP3A genes (which code for enzymes of the same name) is a subfamily of CYP 450 and is involved in the metabolism of about half the drugs on the market today as well as other xenobiotics and steroids.  There are several major genetic polymorphisms in the CYP3A family that can play a role in how a person reacts to a medication.  Additionally, this is another enzyme that can be influenced by drug interactions as well as some foods.

Several fruits – grapefruit, noni, pomegranate – are potent inhibitors of CYP3A4.  Eating or drinking these can cause adverse effects on drug metabolism – either increasing the effect of the drug or decreasing the effect.

Interestingly, CYP3A4 is naturally more active in women than in men.   A long list of drugs metabolized by CYP3A4 is available on Wikipedia.

Check your 23andMe results for rs4987161:

  • GG:  CYP3A4*17, lower function of enzyme, [ref] [ref]
  • AG: carrier of on e CYP3A4*17 allele
  • AA: normal


Check your 23andMe results for rs4986909:

  • AA:  CYP3A4*13, lower function of enzyme, [ref]
  • AG: carrier of on e CYP3A4*13 allele
  • GG: normal


Check your 23andMe results for rs2740574:

  • CC:  CYP3A4*1B, increased risk of ovarian and prostate cancer
  • CT: carrier of on e CYP3A4*1B allele
  • TT: normal


CYP3A5 is another enzyme that is found in the liver, prostate, and intestines.  It metabolizes several types of drugs as well as testosterone, progesterone, and androstenedione.  There are several polymorphisms that reduce the activity of this enzyme significantly. [ref]

Check your 23andMe results for rs41303343:

  • AA:  CYP3A5*7, non-functional
  • -A: carrier of on e CYP3A5*7 allele
  • II: normal


Check your 23andMe results for rs28365083:

  • TT:  CYP3A5*2, non-functional
  • GT: carrier of on e CYP3A5*2 allele
  • GG: normal


Check your 23andMe results for rs776746:

  • CC:  CYP3A5*3, non-functional
  • CT: carrier of on e CYP3A5*3 allele
  • TT: normal


Check your 23andMe results for rs55817950:

  • AA:  CYP3A5*8, non-functional
  • AG: carrier of on e CYP3A4*8 allele
  • GG: normal


Check your 23andMe results for rs28383479:

  • TT:  CYP3A5*9, non-functional
  • CT: carrier of on e CYP3A4*9 allele
  • CC: normal


Check your 23andMe results for rs41279854:

  • GG:  CYP3A5*10, non-functional
  • AG: carrier of on e CYP3A4*10 allele
  • AA: normal


Check your 23andMe results for rs56244447:

  • CC:  CYP3A5*3D, non-functional
  • AC: carrier of on e CYP3A4*3D allele
  • AA: normal



Nrf2 Pathway: Increasing the body’s ability to get rid of toxins

This is part of an ongoing series on the genes involved in detoxification.

The Nrf2 signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. I think of it as flipping the switch to call up the phase II enzymes to take out the trash produced in phase I detox.

The phase II enzymes then further break down the metabolites from phase I detoxification, making them into something that can be excreted by the body.  Specifically, the Nrf2 signaling pathway is involved in GSTs, NQO1, UGTs, and SULTs.


Genetic Variants:

Variants in the NFE2L2 (Nrf2 pathway) gene are fairly common, with some variants increasing Nrf2 pathway signaling and some diminishing it. Some of these are being studied in relation to cancer prognosis, lung volume in smokers, and Parkinson’s disease.

Genetic variants that increase Nrf2:

Check your 23andMe results for rs6726395 (v.4):

  • GG:  greater lung volume in smokers [ref], decreased risk of AMD [ref]
  • AG: somewhat greater lung volume in smokers
  • AA: normal


Check your 23andMe results for rs13001694 (v5):

  • GG: reduced risk of all-cause mortality, especially in smokers [study]
  • AG: reduced risk of all-cause mortality, especially in smokers
  • AA: normal

23andMe results for rs1806649 (v4):

  • CC: normal
  • CT: significantly reduced risk of death from COPD
  • TT: significantly reduced risk of death from COPD (70% reduction) [ref]

Genetic variant that reduces Nrf2 expression:

Check your 23andMe results for rs6721961 (v.4):

  • GG: normal
  • TT: significantly diminished Nrf2 expression, increased risk of lung cancer [ref]


Sulforaphane, a natural substance found in broccoli sprouts, Brussels sprouts, cabbage, cauliflower, activates the Nrf2 pathway. [study][study]  Broccoli sprouts are supposed to be one of the best sources of sulforaphane that you can eat. There are also sulforaphane supplements available. Be sure to get one that includes the myrosinase enzyme such as this one from Jarrow.

Green tea, garlic, turmeric, and DHA also activate Nrf2 to some extent.  [study] [study][study]

More to read:

Video explaining Nrf2: