CYP1A2 inhibition.
We’ve seen in the past studies report that populations of countries which regularly drink kava experience a lower incidence of cancer in that population [1]. It is possible that some of this protection can be explained by the inhibition of certain drug-metabolizing enzymes in the liver.
What are cytochrome P450 enzymes?
We’ve covered this fact before in our series, however these enzymes are extensively involved in a variety of metabolic and biosynthetic processes. Currently there are over 1000 different P450 enzymes identified. These enzymes are primarily responsible for the clearance of xenobiotics. Xenobiotics are any chemical that comes into the body from the environment, and isn’t made endogenously, which are commonly known as “drugs”. These enzymes are thought to be present in every living species on earth [2]. Of the numerous enzymes, we will be focusing on one today, and that’s CYP1A2.
What is CYP1A2 and what does it do?
CYP1A2 is an enzyme found mainly in the liver. This pathway is involved with the metabolization of various drugs and environmental toxins. Specifically 1A2 is involved in the metabolization and activation of aromatic amines and polycyclic aromatic hydrocarbons.
CYP1A2 and Cancer
We now know that CYP1A2 is involved with the metabolism and activation of cancer causing molecules. Aromatic amines and polycyclic aromatic hydrocarbons are well known causative agents in elevated cancer risks [3,4,5]. Increases in CYP1A2 activity have been correlated with an increased risk of breast cancers [6].
CYP1A2 and Caffeine
Interestingly CYP1A2 is also the main pathway of metabolization of caffeine. Routinely caffeine is used to assay CYP1A2 activity [7]. When this enzyme is inhibited caffeine metabolism is reduced and caffeine exerts a longer/stronger effect [8].
CYP1A2 and Tobacco
Clozapine was used to investigate CYP1A2 activity in individuals who smoked tobacco products. It was found CYP1A2 was induced by smoking which caused clozapine to be cleared at a rate 2.5 times that of a non-smoker. It’s clear that smoking tobacco products causes an increase in the activity of this pathway [9,10].
CYP1A2 and Kava
Many studies have shown that kava is a rather potent inhibitor of this specific metabolizing enzyme [11,12,13]. In table 2, the lower the number the more likely for the extract to affect the P450 in question. In table 1 the metabolic ratios of different drugs were studied during kava drinking and 30 days after stopping. Research has discovered kava is inhibiting this pathway no matter which type of product is ingested, however solvent extracts were seen to produce greater inhibition abilities than water extracts.
What does this mean?
Seeing as this enzyme is elevated in smoking and certain cancer states, it lends the possibility that kava, being an inhibitor of CYP1A2 may reduce instances of cancer by inhibiting the activation and metabolization of cancer causing agents in the environment or from tobacco smoke [14]. This certainly doesn’t speak to specific instances of cancer and tumor reduction due to individual fractions of the kava plant, however it may add a little evidence towards kava’s overall chemoprotective effect seen in large kava-drinking populations.
[1] Steiner, G. G. 2000. “The Correlation between Cancer Incidence and Kava Consumption.” Hawaii Medical Journal 59 (11): 420–22.
(https://pubmed.ncbi.nlm.nih.gov/11149250)
[2] Anzenbacher, P., and E. Anzenbacherová. 2001. “Cytochromes P450 and Metabolism of Xenobiotics.” Cellular and Molecular Life Sciences: CMLS 58 (5-6): 737–47.
(https://doi.org/10.1007/pl00000897)
[3] Moorthy, Bhagavatula, Chun Chu, and Danielle J. Carlin. 2015. “Polycyclic Aromatic Hydrocarbons: From Metabolism to Lung Cancer.” Toxicological Sciences: An Official Journal of the Society of Toxicology 145 (1): 5–15.
(https://doi.org/10.1093/toxsci/kfv040.)
[4] Vineis, P., and R. Pirastu. 1997. “Aromatic Amines and Cancer.” Cancer Causes & Control: CCC 8 (3): 346–55. (https://doi.org/10.1023/a:1018453104303)
[5] Wang, Hongge, Zhi Zhang, Sugui Han, Yujuan Lu, Fumin Feng, and Juxiang Yuan. 2012. “CYP1A2 rs762551 Polymorphism Contributes to Cancer Susceptibility: A Meta-Analysis from 19 Case-Control Studies.” BMC Cancer 12 (November): 528.
(https://doi.org/10.1186/1471-2407-12-528)
[6] Hong, Chi-Chen, Bing-Kou Tang, Geoffrey L. Hammond, David Tritchler, Martin Yaffe, and Norman F. Boyd. 2004. “Cytochrome P450 1A2 (CYP1A2) Activity and Risk Factors for Breast Cancer: A Cross-Sectional Study.” Breast Cancer Research: BCR 6 (4): R352–(65. https://doi.org/10.1186/bcr798)
[7] Rizzo, N., E. Hispard, S. Dolbeault, S. Dally, R. Leverge, and C. Girre. 1997. “Impact of Long-Term Ethanol Consumption on CYP1A2 Activity.” Clinical Pharmacology and Therapeutics 62 (5): 505–9.
(https://doi.org/10.1016/S0009-9236(97)90045-X)
[8] Cornelis, Marilyn C., Ahmed El-Sohemy, Edmond K. Kabagambe, and Hannia Campos. 2006. “Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction.” JAMA: The Journal of the American Medical Association 295 (10): 1135–41.
(https://doi.org/10.1001/jama.295.10.1135)
[9] Weide, Jan van der, Linda S. Steijns, and Marga J. van Weelden. 2003. “The Effect of Smoking and Cytochrome P450 CYP1A2 Genetic Polymorphism on Clozapine Clearance and Dose Requirement.” Pharmacogenetics 13 (3): 169–72.
(https://doi.org/10.1097/00008571-200303000-00006)
[10] Zevin, S., and N. L. Benowitz. 1999. “Drug Interactions with Tobacco Smoking. An Update.” Clinical Pharmacokinetics 36 (6): 425–38.
(https://doi.org/10.2165/00003088-199936060-00004)
[11] Anke, Jennifer, and Iqbal Ramzan. 2004. “Pharmacokinetic and Pharmacodynamic Drug Interactions with Kava (Piper Methysticum Forst. F.).” Journal of Ethnopharmacology 93 (2-3): 153–60.
(https://doi.org/10.1016/j.jep.2004.04.009)
[12] Côté, Cynthia S., Christine Kor, Jon Cohen, and Karine Auclair. 2004. “Composition and Biological Activity of Traditional and Commercial Kava Extracts.” Biochemical and Biophysical Research Communications 322 (1): 147–52.
(https://doi.org/10.1016/j.bbrc.2004.07.093)
[13] Mathews, James M., Amy S. Etheridge, and Sherry R. Black. 2002. “Inhibition of Human Cytochrome P450 Activities by Kava Extract and Kavalactones.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 30 (11): 1153–57.
(https://doi.org/10.1124/dmd.30.11.1153)
[14] Russmann, Stefan, Bernhard H. Lauterburg, Yann Barguil, Erwan Choblet, Pierre Cabalion, Katharina Rentsch, and Markus Wenk. 2005. “Traditional Aqueous Kava Extracts Inhibit Cytochrome P450 1A2 in Humans: Protective Effect against Environmental Carcinogens?” Clinical Pharmacology and Therapeutics.
(https://doi.org/10.1016/j.clpt.2005.01.021)
We’ve seen in the past studies report that populations of countries which regularly drink kava experience a lower incidence of cancer in that population [1]. It is possible that some of this protection can be explained by the inhibition of certain drug-metabolizing enzymes in the liver.
What are cytochrome P450 enzymes?
We’ve covered this fact before in our series, however these enzymes are extensively involved in a variety of metabolic and biosynthetic processes. Currently there are over 1000 different P450 enzymes identified. These enzymes are primarily responsible for the clearance of xenobiotics. Xenobiotics are any chemical that comes into the body from the environment, and isn’t made endogenously, which are commonly known as “drugs”. These enzymes are thought to be present in every living species on earth [2]. Of the numerous enzymes, we will be focusing on one today, and that’s CYP1A2.
What is CYP1A2 and what does it do?
CYP1A2 is an enzyme found mainly in the liver. This pathway is involved with the metabolization of various drugs and environmental toxins. Specifically 1A2 is involved in the metabolization and activation of aromatic amines and polycyclic aromatic hydrocarbons.
CYP1A2 and Cancer
We now know that CYP1A2 is involved with the metabolism and activation of cancer causing molecules. Aromatic amines and polycyclic aromatic hydrocarbons are well known causative agents in elevated cancer risks [3,4,5]. Increases in CYP1A2 activity have been correlated with an increased risk of breast cancers [6].
CYP1A2 and Caffeine
Interestingly CYP1A2 is also the main pathway of metabolization of caffeine. Routinely caffeine is used to assay CYP1A2 activity [7]. When this enzyme is inhibited caffeine metabolism is reduced and caffeine exerts a longer/stronger effect [8].
CYP1A2 and Tobacco
Clozapine was used to investigate CYP1A2 activity in individuals who smoked tobacco products. It was found CYP1A2 was induced by smoking which caused clozapine to be cleared at a rate 2.5 times that of a non-smoker. It’s clear that smoking tobacco products causes an increase in the activity of this pathway [9,10].
CYP1A2 and Kava
Many studies have shown that kava is a rather potent inhibitor of this specific metabolizing enzyme [11,12,13]. In table 2, the lower the number the more likely for the extract to affect the P450 in question. In table 1 the metabolic ratios of different drugs were studied during kava drinking and 30 days after stopping. Research has discovered kava is inhibiting this pathway no matter which type of product is ingested, however solvent extracts were seen to produce greater inhibition abilities than water extracts.
What does this mean?
Seeing as this enzyme is elevated in smoking and certain cancer states, it lends the possibility that kava, being an inhibitor of CYP1A2 may reduce instances of cancer by inhibiting the activation and metabolization of cancer causing agents in the environment or from tobacco smoke [14]. This certainly doesn’t speak to specific instances of cancer and tumor reduction due to individual fractions of the kava plant, however it may add a little evidence towards kava’s overall chemoprotective effect seen in large kava-drinking populations.
[1] Steiner, G. G. 2000. “The Correlation between Cancer Incidence and Kava Consumption.” Hawaii Medical Journal 59 (11): 420–22.
(https://pubmed.ncbi.nlm.nih.gov/11149250)
[2] Anzenbacher, P., and E. Anzenbacherová. 2001. “Cytochromes P450 and Metabolism of Xenobiotics.” Cellular and Molecular Life Sciences: CMLS 58 (5-6): 737–47.
(https://doi.org/10.1007/pl00000897)
[3] Moorthy, Bhagavatula, Chun Chu, and Danielle J. Carlin. 2015. “Polycyclic Aromatic Hydrocarbons: From Metabolism to Lung Cancer.” Toxicological Sciences: An Official Journal of the Society of Toxicology 145 (1): 5–15.
(https://doi.org/10.1093/toxsci/kfv040.)
[4] Vineis, P., and R. Pirastu. 1997. “Aromatic Amines and Cancer.” Cancer Causes & Control: CCC 8 (3): 346–55. (https://doi.org/10.1023/a:1018453104303)
[5] Wang, Hongge, Zhi Zhang, Sugui Han, Yujuan Lu, Fumin Feng, and Juxiang Yuan. 2012. “CYP1A2 rs762551 Polymorphism Contributes to Cancer Susceptibility: A Meta-Analysis from 19 Case-Control Studies.” BMC Cancer 12 (November): 528.
(https://doi.org/10.1186/1471-2407-12-528)
[6] Hong, Chi-Chen, Bing-Kou Tang, Geoffrey L. Hammond, David Tritchler, Martin Yaffe, and Norman F. Boyd. 2004. “Cytochrome P450 1A2 (CYP1A2) Activity and Risk Factors for Breast Cancer: A Cross-Sectional Study.” Breast Cancer Research: BCR 6 (4): R352–(65. https://doi.org/10.1186/bcr798)
[7] Rizzo, N., E. Hispard, S. Dolbeault, S. Dally, R. Leverge, and C. Girre. 1997. “Impact of Long-Term Ethanol Consumption on CYP1A2 Activity.” Clinical Pharmacology and Therapeutics 62 (5): 505–9.
(https://doi.org/10.1016/S0009-9236(97)90045-X)
[8] Cornelis, Marilyn C., Ahmed El-Sohemy, Edmond K. Kabagambe, and Hannia Campos. 2006. “Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction.” JAMA: The Journal of the American Medical Association 295 (10): 1135–41.
(https://doi.org/10.1001/jama.295.10.1135)
[9] Weide, Jan van der, Linda S. Steijns, and Marga J. van Weelden. 2003. “The Effect of Smoking and Cytochrome P450 CYP1A2 Genetic Polymorphism on Clozapine Clearance and Dose Requirement.” Pharmacogenetics 13 (3): 169–72.
(https://doi.org/10.1097/00008571-200303000-00006)
[10] Zevin, S., and N. L. Benowitz. 1999. “Drug Interactions with Tobacco Smoking. An Update.” Clinical Pharmacokinetics 36 (6): 425–38.
(https://doi.org/10.2165/00003088-199936060-00004)
[11] Anke, Jennifer, and Iqbal Ramzan. 2004. “Pharmacokinetic and Pharmacodynamic Drug Interactions with Kava (Piper Methysticum Forst. F.).” Journal of Ethnopharmacology 93 (2-3): 153–60.
(https://doi.org/10.1016/j.jep.2004.04.009)
[12] Côté, Cynthia S., Christine Kor, Jon Cohen, and Karine Auclair. 2004. “Composition and Biological Activity of Traditional and Commercial Kava Extracts.” Biochemical and Biophysical Research Communications 322 (1): 147–52.
(https://doi.org/10.1016/j.bbrc.2004.07.093)
[13] Mathews, James M., Amy S. Etheridge, and Sherry R. Black. 2002. “Inhibition of Human Cytochrome P450 Activities by Kava Extract and Kavalactones.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 30 (11): 1153–57.
(https://doi.org/10.1124/dmd.30.11.1153)
[14] Russmann, Stefan, Bernhard H. Lauterburg, Yann Barguil, Erwan Choblet, Pierre Cabalion, Katharina Rentsch, and Markus Wenk. 2005. “Traditional Aqueous Kava Extracts Inhibit Cytochrome P450 1A2 in Humans: Protective Effect against Environmental Carcinogens?” Clinical Pharmacology and Therapeutics.
(https://doi.org/10.1016/j.clpt.2005.01.021)
