CYP3A4 is an important CYP enzyme, responsible for clearing approximately 45 – 60% of currently prescribed drugs. Different supplements, food additives, and other substances can decrease CYP3A4 activity and, as a result, interfere with drug metabolism. Find out more about CYP3A4 function, gene variants, and supplements that can increase or decrease CYP3A4 activity.
What is CYP3A4?
- Opioids: sufentanil  and methadone 
- Immune suppressants: cyclosporine , tacrolimus , and sirolimus 
- Antihypertensive drugs: felodipine  and nifedipine 
- Anticancer drugs: endoxifen , tamoxifen , and sunitinib 
- Sedatives: midazolam 
- Cholesterol-lowering drugs (statins): simvastatin , atorvastatin, and lovastatin 
- Antibiotics: erythromycin 
- Corticosteroids: fluticasone propionate 
- Metabolizes many internal compounds such as cholesterol, fatty acids, prostaglandins, leukotrienes, retinoids and biogenic amines .
- Detoxifies bile acids and decreases their toxicity .
- Deactivates testosterone to biologically less active metabolites .
- Partly degrades vitamin D .
The activity of this enzyme varies up to 40-fold and is affected by health, environment (smoking, diet, and co-medication), hormones, and genetics .
CYP3A4 is the most active CYP enzyme in the gut . Therefore it is not surprising that what we eat and drink has a great effect on the activity of this enzyme.
Components in foods, drinks, food additives, and other drugs usually decrease CYP3A4 activity producing one of the following effects:
- Decreasing the inactivation or degradation of the drug, thus, increasing the actual dose of the active form in the blood, which often causes unfavorable and long-lasting effects .
- Decreasing the activation of some those medications that are administered as a pro-drug, thus, decreasing the actual dose of the active form of the drug that reaches the blood, which decreases the biological efficacy of the drug .
Increasing or Decreasing CYP3A4
These increase CYP3A4:
- St. John’s wort [14, 15, 16]
- Capsaicin [17, 18]
- Common valerian 
- Echinacea purpurea 
- Vitamin D and UV exposure 
- Being female 
- Diabetes 
- Fatty acids 
- Polycyclic aromatic hydrocarbons (PAH) found in cigarettes 
- Aflatoxin B1 
- Some drugs such as carbamazepine  and dexamethasone 
These decrease CYP3A4:
- Grapefruit juice (and its compounds bergamottin, naringenin, and paradicin-A) [26, 4, 27]
- Starfruit juice 
- Aloe vera juice 
- Mixed vegetable juices 
- Kale 
- Garden cress [32, 33]
- Goldenseal 
- Fennel 
- Raspberry leaf 
- Quercetin [36, 37, 38]
- Kaempferol 
- Berberine [39, 40]
- Piperine, a constituent of black pepper [41, 42]
- Licochalcone A, a compound in traditional Chinese herbal licorice 
- Oleuropein, derived from olive oil 
- Sesamin found in sesame seeds (Sesamum indicum) 
- Resveratrol [33, 45, 4]
- Sulforaphane 
- Apigenin 
- Coumestrol 
- Caffeic acid [37, 4]
- Tannic acid 
- Gallic acid [4, 48]
- Allyl isothiocyanate 
- Ginsenoside Rd , derived from Ginseng
- Milk thistle (compounds silybin and isosilybin) 
- Gomisin C and gomisin G found in the traditional Chinese medicine Schisandra Chinensis 
- Green tea flavonols epigallocatechin gallate and epicatechin gallate [4, 53]
- Crohn’s disease 
- Drugs ritonavir, itraconazole , miconazole, ketoconazole , verapamil , sertraline , metformin , nefazodone , and clarithromycin 
CYP3A4 Genetic Variants
Unlike variable enzymes such as CYP2D6, CYP2C9 or CYP2C19, the CYP3A4 enzyme has fewer gene variants, and only a few of them are known to influence enzyme function .
Most of the SNPs (around 20) found in this enzyme have no functional significance .
Also known as CYP3A4*22 (T), rs35599367 is associated with decreased enzyme activity .
T/T people have around 2 times lower enzyme activity .
People with this variant require a 40% lower dose of simvastatin (830 subjects) .
Children on fluticasone propionate with CYP3A4*22 have improved asthma control (734 patients) .
CYP3A4*22 carriers were less likely to have severe hot flashes as side effects on tamoxifen therapy (132 patients) .
rs2740574 can increase the risk of methadone overdose and fatalities (228 cases) .
G variant increases prostate cancer susceptibility (meta-analysis, 39 studies, 14,334 cases, and 18,183 controls) .
Individual carrying G have a 3 times greater risk of developing lung cancer (106 patients and 116 controls) .
This SNP is commonly found in Asians .
There is an association between the G variant of rs680055 and the probability of developing prostate cancer (240 patients and 223 controls) .