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CYP3A4 Enzyme: The Grapefruit Effect

Written by Biljana Novkovic, PhD | Last updated:

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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?

CYP3A4 is one of the cytochrome P450 monooxygenases (CYPs), which are enzymes that eliminate most of the drugs and toxins from our body [1].

This enzyme is one of the most important CYP enzymes since it is responsible for processing approximately 45–60% of prescribed drugs [2, 3]:

  • Opioids: sufentanil [2] and methadone [3]
  • Immune suppressants: cyclosporine [4], tacrolimus [5], and sirolimus [6]
  • Antihypertensive drugs: felodipine [4] and nifedipine [7]
  • Anticancer drugs: endoxifen [7], tamoxifen [8], and sunitinib [7]
  • Sedatives: midazolam [7]
  • Cholesterol-lowering drugs (statins): simvastatin [9], atorvastatin, and lovastatin [7]
  • Antibiotics: erythromycin [5]
  • Corticosteroids: fluticasone propionate [7]

CYP3A4 also:

  • Metabolizes many internal compounds such as cholesterol, fatty acids, prostaglandins, leukotrienes, retinoids and biogenic amines [10].
  • Detoxifies bile acids and decreases their toxicity [10].
  • Deactivates testosterone to biologically less active metabolites [11].
  • Partly degrades vitamin D [6].

This enzyme degrades the majority of drugs and cancer-causing agents, to protect cells and the body from toxins [10, 12].

The activity of this enzyme varies up to 40-fold and is affected by health, environment (smoking, diet, and co-medication), hormones, and genetics [3].

Nuclear receptors PXR and CAR activate CYP3A4 [10].

CYP3A4 Location

This enzyme is mainly found in the liver (∼40% of the total liver CYP content) but also in the small intestine, prostate, breast, colon, and brain [7, 6, 43].

CYP3A4 is the most active CYP enzyme in the gut [6]. 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 [4].
  • 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 [13].

Increasing or Decreasing CYP3A4

These increase CYP3A4:

  • St. John’s wort [14, 15, 16]
  • Capsaicin [17, 18]
  • Common valerian [19]
  • Echinacea purpurea [20]
  • Vitamin D and UV exposure [6]
  • Being female [21]
  • Diabetes [22]
  • Fatty acids [22]
  • Polycyclic aromatic hydrocarbons (PAH) found in cigarettes [23]
  • Aflatoxin B1 [24]
  • Some drugs such as carbamazepine [10] and dexamethasone [25]

These decrease CYP3A4:

  • Grapefruit juice (and its compounds bergamottin, naringenin, and paradicin-A) [26, 4, 27]
  • Starfruit juice [28]
  • Aloe vera juice [29]
  • Mixed vegetable juices [30]
  • Kale [31]
  • Garden cress [32, 33]
  • Goldenseal [34]
  • Fennel [35]
  • Raspberry leaf [35]
  • Quercetin [36, 37, 38]
  • Kaempferol [36]
  • Berberine [39, 40]
  • Piperine, a constituent of black pepper [41, 42]
  • Licochalcone A, a compound in traditional Chinese herbal licorice [43]
  • Oleuropein, derived from olive oil [41]
  • Sesamin found in sesame seeds (Sesamum indicum) [44]
  • Resveratrol [33, 45, 4]
  • Sulforaphane [46]
  • Apigenin [4]
  • Coumestrol [47]
  • Caffeic acid [37, 4]
  • Tannic acid [4]
  • Gallic acid [4, 48]
  • Allyl isothiocyanate [49]
  • Ginsenoside Rd [50], derived from Ginseng
  • Milk thistle (compounds silybin and isosilybin) [51]
  • Gomisin C and gomisin G found in the traditional Chinese medicine Schisandra Chinensis [52]
  • Green tea flavonols epigallocatechin gallate and epicatechin gallate [4, 53]
  • Crohn’s disease [54]
  • Drugs ritonavir, itraconazole [55], miconazole, ketoconazole [56], verapamil [57], sertraline [58], metformin [59], nefazodone [60], and clarithromycin [61]

Curcumin has a paradoxical effect, since it both increases and decreases the activity of CYP3A4 [62, 63, 64].

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 [7].

Most of the SNPs (around 20) found in this enzyme have no functional significance [7].

  • RS35599367

Also known as CYP3A4*22 (T), rs35599367 is associated with decreased enzyme activity [5].

It is found in 4-8% of the population [7, 5].

T/T people have around 2 times lower enzyme activity [5].

People with this variant require a 40% lower dose of simvastatin (830 subjects) [9].

Children on fluticasone propionate with CYP3A4*22 have improved asthma control (734 patients) [65].

CYP3A4*22 carriers were less likely to have severe hot flashes as side effects on tamoxifen therapy (132 patients) [8].

  • RS2740574

rs2740574 is frequent (50-82%) in Africans and African Americans, but rare (3-5%) in Whites [7]. Functional significance is unknown.

rs2740574 can increase the risk of methadone overdose and fatalities (228 cases) [3].

G variant increases prostate cancer susceptibility (meta-analysis, 39 studies, 14,334 cases, and 18,183 controls) [66].

Individual carrying G have a 3 times greater risk of developing lung cancer (106 patients and 116 controls) [67].

  • RS2242480

This SNP is commonly found in Asians [2].

rs2242480 was associated with more frequent methadone overdose fatalities (228 cases) [3].

  • RS680055

There is an association between the G variant of rs680055 and the probability of developing prostate cancer (240 patients and 223 controls) [11].

About the Author

Biljana Novkovic

Biljana Novkovic

PhD
Biljana received her PhD from Hokkaido University.
Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science and health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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