CYP3A4 and CYP3A5: How genes impact prescription medications

Our bodies break down (metabolize) drugs and other toxins through a group of enzymes known as the CYP450 family. Different CYP enzymes break down different substances, and we all carry genetic variants that can impact whether we metabolize a drug quickly or slowly.

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.

Several fruits – grapefruit, noni, pomegranate – are potent inhibitors of CYP3A4.  Eating or drinking these can cause adverse effects on drug metabolism, either increasing the efficiency 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 Pharmacy Times and on  Wikipedia.

Commonly prescribed drugs metabolized by CYP3A4 include:

  • Viagra
  • Xanax
  • Cialis
  • Zocor
  • Prednisone

Methadone dosages can also be impacted by this gene.[ref]


CYP3A4 Gene Variants:

Check your genetic data for rs4987161 (23andMe v4, v5):

  • G/G: CYP3A4*17, decreased function of enzyme, [ref] [ref]
  • A/G: carrier of one CYP3A4*17 allele
  • A/A: normal

Check your genetic data for rs4986909 (23andMe v4; AncestryDNA):

  • A/A: CYP3A4*13, decreased function of the enzyme, [ref]
  • A/G: carrier of one CYP3A4*13 allele
  • G/G: normal

Check your genetic data for rs2740574 (23andMe v4,v5; AncestryDNA):

  • C/C: CYP3A4*1B, decreased function of the enzyme [ref]
  • C/T: carrier of one CYP3A4*1B allele
  • T/T: normal

Check your genetic data for rs4986910 (23andMe v4, v5):

  • G/G: CYP3A4*3, decreased function
  • A/G: carrier of one CYP3A4*3 allele
  • A/A: normal

Check your genetic data for rs4986907 (23andMe v4, v5):

  • T/T: CYP3A4*15A, decreased function
  • C/T: carrier of one CYP3A4*15A allele
  • C/C: normal

 


CYP3A5 Gene Variants:

CYP3A5 is another enzyme that is found in the liver, prostate, and intestines. The vast majority of Caucasians have a genetic variant (rs776746) that decreases the functionality of this enzyme.

Most of the drugs metabolized through CYP3A4 are also metabolized by CYP3A5. So if you are a poor or non-functioning CYP3A5 metabolizer but have functioning CYP3A4 genes, you may be just fine. 

Since the majority of several populations have the non-functioning variants, for this gene NOT carrying a variant may impact your metabolism of certain drugs by increasing enzyme function.[ref]

In addition to several types of drugs, CYP3A5 also metabolizes testosterone, progesterone, and androstenedione.[ref]

Check your genetic data for rs776746  (23andMe v4, v5; AncestryDNA):

  • C/C:  CYP3A5*3, non-functional –most common type in Caucasians–
  • C/T: carrier of only one CYP3A5*3 allele (thus some CYP3A5 function)
  • T/T: normal function

 

Check your genetic data for rs41303343 (23andMe v4 only):

  • A/A:  CYP3A5*7, non-functional
  • -A: carrier of one CYP3A5*7 allele (thus some CYP3A5 function)
  • II: normal function

 

Check your genetic data for rs28365083 (23andMe v4, v5; AncestryDNA):

  • T/T:  CYP3A5*2, non-functional
  • G/T: carrier of one CYP3A5*2 allele (thus some CYP3A5 function)
  • G/G: normal function

 

Check your genetic data for rs55817950 (23andMe v4, v5; AncestryDNA):

  • A/A:  CYP3A5*8, non-functional
  • A/G: carrier of one CYP3A4*8 allele (thus some CYP3A5 function)
  • G/G: normal function

 

Check your genetic data for rs28383479 (23andMe v4, v5):

  • T/T:  CYP3A5*9, non-functional
  • C/T: carrier of one CYP3A4*9 allele
  • C/C: normal

 

Check your genetic data for rs41279854 (23andMe v4, v5; AncestryDNA):

  • G/G:  CYP3A5*10, non-functional
  • A/G: carrier of one CYP3A4*10 allele (thus some CYP3A5 function)
  • A/A: normal function

 

Check your genetic data for rs56244447 (23andMe v4, v5; AncestryDNA):

  • C/C:  CYP3A5*3D, non-functional
  • A/C: carrier of one CYP3A4*3D allele (thus some CYP3A5 function)
  • A/A: normal function


Lifehacks

If you carry one or two copies of a CYP3A4 variant that is non-functioning, this may impact the way medications work for you.  Look through the list of drugs metabolized by this enzyme and talk with your doctor or pharmacist.  (Keep in mind that 23andMe and AncestryDNA do not guarantee the accuracy for medical purposes. Your doctor may want to run a second test.)

Grapefruit, noni, and pomegranate juices are inhibitors of CYP3A4 and CYP3A5. If you carry any of the genetic variants above for CYP3A4, be very careful of these juices or other inhibitors when taking a medication that is metabolized through CYP3A4.

St. John’s Wort is an inducer of CYP3A4, meaning it causes more of the enzyme to be created in the body. If you are taking a drug that is metabolized by CYP3A4, then you need to be careful with St. John’s wort interacting with the medication. (Talk with a doctor or pharmacists)[ref]

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

 



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