Cytochrome P450

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Cytochrome P450 3A4 enzyme complex

Cytochrome P450 is a family of enzymes mainly responsible for the degradation of substances. It accounts for about 75% of the total metabolism in the human body.[1]

Some substances can modulate the activity of CYP enzymes by either inducing or directly inhibiting the activity of CYP. This is a major source of adverse substance reactions, as changes in CYP enzyme activity can affect metabolism and release of various substances.

For example, if one substance inhibits the CYP-mediated metabolism of another substance, the second substance may accumulate in the body in toxic amounts. Therefore, these substance interactions may require dosage adjustment or the selection of substances that do not interact with the CYP system.

Substrates

Inhibitors

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Some CYP450 inhibitors are also MAOIs.

Make sure to check our list of MAOI interactions that can be dangerous.

Cytochrome P450 inhibitors inhibit the ability of the human body to break down certain substances, potentially increasing the amount of time a substance is active in the body.

In some cases, this inhibition of how substances are broken down in the body can lead to dangerous adverse effects. Under some conditions, this can be fatal.

CYP450 inhibitors (CYP2B6 = CYP450 2B6, CYP2C19 = CYP450 2C19, etc)

Role in synthetic pathways

The function of cytochromes P450 is not limited to degradation. Some members of the CYP family are responsible for important biosynthetic pathways in animals, plants, fungi and bacteria. An example of such enzyme in humans is CYP19A1, more commonly known as aromatase, which catalyzes the synthesis of estradiol from testosterone [19].

Plants and fungi often use CYP in some steps of the syntheses of their secondary metabolites, many of which are used in medicine (and psychonautics). Researchers around the world study them with the goal of developing ways to engineer CYP and use it to make the production of such compounds easier [20].

Some examples of natural compounds with biosynthetic pathways involving CYP:

  • Morphine: CYP719B1 (salutaridine synthase) catalyzes C-C phenol coupling [21]
  • Cocaine: Recently discovered CYP81AN15 catalyzes the formation of tropane ring in E. novogranatense [22]
  • Related plants, such as datura, use analogous CYPs for tropane synthesis

See also

External links

References

  1. ↑ Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology". Chemical Research in Toxicology. 21 (1): 70–83. doi:10.1021/tx700079z. PMID 18052394. 
  2. ↑ 2.0 2.1 Gates, S., Miners, J. O. (March 1999). "Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism". British Journal of Clinical Pharmacology. 47 (3): 299–305. doi:10.1046/j.1365-2125.1999.00890.x. ISSN 0306-5251. 
  3. ↑ 3.0 3.1 3.2 3.3 https://drug-interactions.medicine.iu.edu/clinical-table.aspx
  4. ↑ Tsukamoto, S., Aburatani, M., Ohta, T. (June 2005). "Isolation of CYP3A4 Inhibitors from the Black Cohosh (Cimicifuga racemosa)". Evidence-based Complementary and Alternative Medicine. 2 (2): 223–226. doi:10.1093/ecam/neh086. ISSN 1741-427X. 
  5. ↑ Jiang, R; Yamaori, S; Okamoto, Y; Yamamoto, I; Watanabe, K (2013). "Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19". Drug metabolism and pharmacokinetics. 28 (4): 332–8. doi:10.2133/dmpk.dmpk-12-rg-129. PMID 23318708. 
  6. ↑ 6.0 6.1 Qian, Y; Gurley, BJ; Markowitz, JS. "The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications". Journal of clinical psychopharmacology. 39 (5): 462–471. doi:10.1097/JCP.0000000000001089. PMID 31433338. 
  7. ↑ Yamaori, S; Okamoto, Y; Yamamoto, I; Watanabe, K (November 2011). "Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6". Drug metabolism and disposition: the biological fate of chemicals. 39 (11): 2049–56. doi:10.1124/dmd.111.041384. PMID 21821735. 
  8. ↑ "Epidiolex (Cannabidiol) FDA Label" (PDF). US Food and Drug Administration (FDA). Retrieved June 28, 2018.  For label updates see FDA index page for NDA 210365
  9. ↑ Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (March 2007). "Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes". Life Science. 80 (15): 1415–9. doi:10.1016/j.lfs.2006.12.032. PMID 17303175. 
  10. ↑ https://drug-interactions.medicine.iu.edu/clinical-table.aspx
  11. ↑ Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Khan IA, Shah A (2005). "In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes". Clin. Pharmacol. Ther. 77: 415–26. doi:10.1016/j.clpt.2005.01.009. PMC 1894911 Freely accessible. PMID 15900287. 
  12. ↑ Leclercq, Isabelle; Desager, Jean-Pierre; Horsmans, Yves (1998). "Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress". Clinical Pharmacology & Therapeutics. 64 (2): 144–9. doi:10.1016/S0009-9236(98)90147-3. PMID 9728894. 
  13. ↑ Wenk M, Todesco L, Krähenbühl S (2004). "Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females" (PDF). Br J Clin Pharmacol. 57 (4): 495–499. doi:10.1111/j.1365-2125.2003.02049.x. PMC 1884478 Freely accessible. PMID 15025748. 
  14. ↑ Zhang, J.-W., Liu, Y., Cheng, J., Li, W., Ma, H., Liu, H.-T., Sun, J., Wang, L.-M., He, Y.-Q., Wang, Y., Wang, Z.-T., Yang, L. (2007). "Inhibition of human liver cytochrome P450 by star fruit juice". Journal of Pharmacy & Pharmaceutical Sciences: A Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne Des Sciences Pharmaceutiques. 10 (4): 496–503. doi:10.18433/j30593. ISSN 1482-1826. 
  15. ↑ 15.0 15.1 15.2 Zhao, T., He, Y., Wang, J., Ding, K., Wang, C., Wang, Z. (November 2011). "Inhibition of human cytochrome P450 enzymes 3A4 and 2D6 by β-carboline alkaloids, harmine derivatives". Phytotherapy research: PTR. 25 (11): 1671–1677. doi:10.1002/ptr.3458. ISSN 1099-1573. 
  16. ↑ Gram, L. F., Guentert, T. W., Grange, S., Vistisen, K., Brøsen, K. (June 1995). "Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study". Clinical Pharmacology and Therapeutics. 57 (6): 670–677. doi:10.1016/0009-9236(95)90230-9. ISSN 0009-9236. 
  17. ↑ Bhardwaj, R. K., Glaeser, H., Becquemont, L., Klotz, U., Gupta, S. K., Fromm, M. F. (August 2002). "Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 645–650. doi:10.1124/jpet.102.034728. ISSN 0022-3565. 
  18. ↑ Elbarbry, F., Ung, A., Abdelkawy, K. (2017). "Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities". Pharmacognosy Magazine. 13 (Suppl 4): S895–S899. doi:10.4103/0973-1296.224342. ISSN 0973-1296. 
  19. ↑ https://www.uniprot.org/uniprotkb/P11511/entry
  20. ↑ Liu, X., Zhu, X., Wang, H., Liu, T., Cheng, J., & Jiang, H. (2020). Discovery and modification of cytochrome P450 for plant natural products biosynthesis. In Synthetic and Systems Biotechnology (Vol. 5, Issue 3, pp. 187–199). Elsevier BV. https://doi.org/10.1016/j.synbio.2020.06.008
  21. ↑ Liu, X., Zhu, X., Wang, H., Liu, T., Cheng, J., & Jiang, H. (2020). Discovery and modification of cytochrome P450 for plant natural products biosynthesis. In Synthetic and Systems Biotechnology (Vol. 5, Issue 3, pp. 187–199). Elsevier BV. https://doi.org/10.1016/j.synbio.2020.06.008
  22. ↑ Yong-Jiang Wang, Jian-Ping Huang, Tian Tian, Yijun Yan, Yin Chen, Jing Yang, Jianghua Chen, Yu-Cheng Gu, and Sheng-Xiong Huang , Discovery and Engineering of the Cocaine Biosynthetic Pathway, Journal of the American Chemical Society 2022 144 (48), 22000-22007 DOI: 10.1021/jacs.2c09091
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