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]

 


Lifehacks:

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

Lifehacks

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:

 

Liver Detox Genes – CYP2D6

How we differ in our abilities to detox drugs, toxins, and our own hormones
How we differ in our abilities to detox drugs, toxins, and our own hormones.
Img. by Tareq Saluhuddin

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

The CYP2D6 enzymes metabolize about 25% of pharmaceutical drugs such as SSRI’s, opioids, tamoxifen, Nyquil, and beta blockers. It also metabolizes serotonin and neurosteroids (pregnenolone, cholesterol, androsterone, etc).

There are several important polymorphisms in CYP2D6 which cause either extensive or very poor metabolism – or something in between.  There are both good and bad potential consequences of being a poor or extensive metabolizer.  Being a poor metabolizer may reduce the risk of some cancers such as bladder or lung.  On the other hand, it also may significantly increase the risk of Parkinson’s disease for those exposed to pesticides.

Knowing whether you’re a fast or slow metabolizer may make it easier to find the right dosage of certain medications.  There is a good list of drugs (substrates) metabolized by CYP2D6 on Wikipedia.

Check your 23andMe results for rs3892097:

  •  TT: CYP2D6*4 – poor metabolizer
  • CT:  typically intermediate metabolizer
  •  CC: extensive metabolizer

 

Check your 23andMe results for rs5030655

  •  – – : CYP2A6*6 – deletion, poor metabolizer

 

Check your 23andMe results for rs1065852:

  • AA: decreased or non-functioning
  • AG:  somewhat decreased
  • GG: normal

 

Check your 23andMe results for rs1135824:

  •  TT: normal
  • CT:  one copy of CYP2D6*3
  •  CC: two copies of CYP2D6*3, non-functioning

 

Check your 23andMe results for rs5030867:

  •  TT: normal
  • GT:  carrier of one CYP2D6*7 allele
  • GG: carrier of two CYP2D6*7, non-functioning

 

Check your 23andMe results for rs5030656:

  •  I I: normal
  • – I:  carrier of one CYP2D6*9 allele
  • – -: carrier of two CYP2D6*9, non-functioning

 

Check your 23andMe results for rs28371706:

  •  GG: normal
  •  AG:  carrier of one decreased or non-functioning allele
  •   AA: possibly decreased or non-functioning

There are many other, less common variants for CYP2D6. You can check on CYP2D6 on SNPedia for more information.

Liver Detox Genes – CYP2A6

Liver DetoxGenesThis is part of an ongoing series on the genes involved in Phase I detoxification.

The CYP2A6 enzyme is involved in the metabolism of nicotine, several cancer drugs,  valproic acid, and coumarin. (Full list of drugs on Wikipedia). The hormone estradiol is an inducer of CYP2A6, and women usually have a somewhat higher activity of this enzyme.

It is thought that variant of CYP2A6 that cause decreased activity causes a lower level of dependence in smokers, making it easier for them to quit.  On the other hand, those with increased enzyme activity have an enhanced metabolism of nicotine and are likely to smoke more cigarettes per day.  [ref]

There are quite a few variations of CYP2A6.  Below are just a few that are available with 23andMe v.4 raw data.  For more information on CYP2A6 check out the PharmG KB site.

Check your 23andMe results for rs1801272: (note: 23andMe orientation – plus)

  • TT: CYP2A6*2 – reduced activity [study]
  • AT:  One CYP2A6*2 allele, reduced activity
  • AA: normal

 

Check your 23andMe results for rs5031017:

  • AA: CYP2A6*5 – non-functioning variant [study]
  • AC:  One CYP2A6*5 allele, reduced activity
  • CC: normal

 

Check your 23andMe results for rs5031016:

  • GG: CYP2A6*7 – non-functioning variant [study]
  • AG:  One CYP2A6*7 allele, reduced activity
  • AA: normal

 

Check your 23andMe results for rs28399444:

  •  – – : CYP2A6*20 – non-functioning variant [study]
  • – I:  One CYP2A6*20 allele, reduced activity
  •  II: normal

Diet and Supplements:

Grapefruit juice contains a substance that inhibits CYP2A6 enzyme activity.  So be careful – especially if you have a slow variant of the gene – with combining grapefruit juice with any drug that is metabolized by CYP2A6.

More to read:

 

CYP1A2 – Breaking down caffeine and more

 

This is part of a series on genes involved in detoxification.

The CYP1A2 enzyme is involved in the metabolism of xenobiotics (caffeine, aflatoxin B1, and acetaminophen) and is induced by the polycyclic aromatic hydrocarbons (PAH’s) that are found in cigarette smoke.  It metabolizes some pro-carcinogens into carcinogenic intermediates.

CYP1A2 is also induced (activated) by cruciferous veggies such as cabbage, cauliflower, and broccoli.  It is inhibited by cumin, turmeric, peppermint, chamomile, dandelion, and St. John’s wort.  There is a list of drugs, inducers, and inhibitors of CYP1A2 on Wikipedia.  Popular drugs that are metabolized, at least partially,  by CYP1A2 include Wellbutrin, Zyprexa, and Cymbalta — as well as caffeine.

In looking at CYP1A2, there are several genetic variants that either increase the activity or decrease the activity of this enzyme.  So what are the consequences of inhibited or increased activity?  Well, it depends on what substance you are breaking down. CYP1A2 metabolizes some pro-carcinogens from tobacco smoke into carcinogens.  It also is involved in turning aflatoxins (mold found on grain) into active compounds involved in liver cancer.  So the rate at which the toxins are metabolized, in conjunction with how well Phase II detoxification is doing at moving out the metabolites, all affect the risk of certain cancers. For example, slow or inactive CYP1A2 is thought to decrease the risk of liver toxicity from aflatoxin B. This is because CYP1A2 turns the pro-carcinogenic molecules into carcinogens, which then have to be removed from the body.

One of the fun things to find out from your CYP1A2 genes is whether you are a fast or slow metabolizer of caffeine.  (Of course, you probably already know how you react to caffeine, but it is nice to see the science behind it :-)

Check your 23andMe results for rs762551 (v4, v5):

  • AA: Fast metabolizer of caffeine – increased CYP1A2 activity
  • AC:  medium caffeine metabolizer [study]
  • CC: slower caffeine metabolizer (CYP1A2*1F)

Studies on this variant show:

  • increased risk of esophageal cancer for those with AA, especially with salt tea consumption.[ref]
  • lower blood pressure for those carrying the variant (AA, AC), but only in non-smokers[ref]
  • people carrying the variant (AA, AC) tend to drink more coffee[ref]
  • Asians carrying the variant are at a slightly lower risk of colon cancer[ref]

 

Other CYP1A2 variants have also been shown to decrease the activity of this gene as well:

Check your 23andMe results for rs12720461:

  • CC: normal
  • CT:  decreased activity (carrier of one CYP1A2*1K allele)
  • TT: decreased activity (CYP1A2*1K )

 

Check your 23andMe results for rs72547517 (v4, v5):

  • AA: decreased activity or inactive (CYP1A2*8)
  • AG:  decreased activity (carrier of one CYP1A2*8 allele)
  • GG: normal

 

Check your 23andMe results for rs72547515 (v4,v5):

  • AA: decreased activity or inactive (CYP1A2*16)
  • AG:  decreased activity (carrier of one CYP1A2*16 allele)
  • GG: normal

 


Lifehacks:

Your genetic variants are estimated to determine about 75% of your CYP1A2 enzyme activity,  with food, supplements, and smoking impacting about 25% of the enzyme activity level.[ref]  If you are taking a drug, such as Clozapine,  that is metabolized by CYP1A2, you should look at both your genetics and at what you are eating and/or smoking.

Curcumin is an inhibitor of CYP1A2 in humans and in animals.  A recent animal study found that curcumin prevented liver damage from aflatoxin B exposure.  A potent carcinogen, aflatoxin B is a toxin produced by mold (Aspergillus) and sometimes found in peanuts, corn, and other grains.  Curcumin can be taken as a supplement and is also found in the spice, turmeric.

Other inhibitors of CYP1A2 include ciprofloxacin (antibiotic) and cimetidine (aka Tagamet).[ref]  So keep in mind that your caffeine metabolism may be altered when taking a CYP1A2 inhibitor.  In other words, if you are normally a fast metabolizer and drink coffee or tea with dinner, you may find yourself having problems sleeping if you couple that caffeine with a CYP1A2 inhibitor like Tagamet, curcumin, or ciprofloxacin.

More to Read:

CYP1A1: Detoxifying Cigarette Smoke and Estrogen

This is part of a series on the genes involved in phase I and phase II detoxification.

CYP1A1 is a gene that codes for an enzyme that breaks down (metabolizes) a few different substances.  It is involved in the metabolism of poly-aromatic hydrocarbons (PAH) in the intestines, thus playing a role in smoking-related cancers from the activation of the aromatic hydrocarbons. Aromatic hydrocarbons are also found in wood smoke, vehicle exhausts, asphalt, and charred meats.

In addition to toxins we may breathe in or eat, CYP1A1 is also involved in the metabolism of estrogen – specifically 17β-estradiol – as well as arachidonic acid and DHA (fatty acids).

There are several genetic variants of CYP1A1 that can change the speed at which your body will metabolize substances. Increased CYP1A1 metabolism can cause the buildup of the intermediate metabolites if your body can’t get rid of them fast enough through phase II metabolism.

Recap: CYP1A1 breaks down aryl hydrocarbons (in cigarette smoke), turning it into an even more carcinogenic compound. Genetic variants that speed up CYP1A1 create the carcinogenic metabolites faster than the body can get rid of them, thus increasing cancer risk.

CYP1A1*2:

Check your 23andMe results for rs1048943 (v.4 only):

  • TT: Normal
  • CT:  carrier of one CYP1A1*2 allele; smokers have higher risk of lung cancers; higher activity in estrogen metabolism
  • CC: CYP1A1*2; higher risk of oral cancer & lung cancers in smokers; higher activity in estrogen metabolism [study],[study], [study]

There are several studies showing a relationship between the CYP1A1*2 (C allele) and estrogen-related cancers, but the results vary according to population and possibly diet:

  • A Chinese study showed that the CYP1A1*2 polymorphism had a lower risk of breast cancer.
  •  Another study showed that those with CYP1A1*2 have more of an inhibition with natural polyphenols than those without the polymorphism.
  • study showed that CYP1A1*2 has a significantly higher activity level of estrogen metabolism.   “Taken together, from a biochemical point of view, the extraordinary high estrogen-2-hydroxylase activity of the CYP1A1.2 (Ile562Val) variant may either increase or reduce the susceptibility to cancer depending on its combination with other genetic and environmental risk factors…”

Diet plays a role here as well.  A study found that those with the CYP1A1*2  variant had a greater reduction in colon cancer risk with a diet high in polyphenols (found in veggies and fruit) than those without the variant.

Other genes, such as COMT, also come into play when looking at estrogen-related cancer risk. One speculation is that: “Considering the metabolic fate of the 2-hydroxyestrogens produced by CYP1A1, a particular risk may arise if CYP1A1*2 (Ile462Val) occurs simultaneously with both (a) a “low-activity” COMT allele (COMT-L, 108/158Met substitution), and/or (b) a defect in one of the glutathione-S-transferase (GST) genes required to detoxify the quinones by conjugation with glutathione (e.g., in carriers of the GSTM1 and/or GSTT1 null genotypes). In theory, this combination would cause an accumulation of 2-hydroxylated” [study]
You can check your COMT genetic variants here: COMT – Genetic Connection to Neurotransmitter Levels

 

CYP1A1*4:
The CYP1A1*4 variant has a somewhat increased enzyme activity.  Some studies show it to be protective against certain cancers, and other show it to slightly increase risk depending on the population.[study] [study]  One reason for the conflicting studies may be because it is fairly rare to have a homozygous (TT) mutation, and the percentage of heterozygotes (GT) in Caucasian populations is less than 10%.

Some studies show that the CYP1A1*4 allele is protective against lung cancer.[study] A meta-analysis found it to be a risk factor for thyroid cancer.[study]

Check your 23andMe results for rs1799814 (v.4 and v.5):

  • GG: Normal
  • GT: one CYP1A1*4 allele
  • TT: increased enzyme activity, CYP1A1*4 [study]

Diet and Lifestyle:

Those who have a CYP1A1*2 allele are likely at a higher risk for lung cancer and really, really should not smoke. So if you need yet another reason to stop smoking, this would be a big one.

CYP1A1 is inhibited by several natural polyphenols including St. John’s Wort, I3C, and resveratrol.[study] Foods containing I3C include broccoli and other cruciferous vegetables.  Resveratrol is found in grapes and red wine as well as in supplement form.

Grapefruit juice also inhibits CYP1A1.[ref]

Camel milk inhibits CYP1A1.  Interestingly, camel milk has traditionally been thought to be protective against cancer in the Middle East.  Looks like for smoker’s with CYP1A1*2 variants, it could actually reduce the high risk of lung cancer.[ref]