Many environmental toxins, drugs and hormones are going through liver Phase I to Phase II of detoxification. The first line of defence is Phase I detoxification. There are enzymes, known as cytochrome P-450 system that modify toxic compounds, drugs, and steroid hormones. In Phase II detoxification, most of toxins, drugs and hormones go to modification and become more water soluble and ready for elimination through urine and bile (into feces). Increase of Phase I clearance, without increase of Phase II clearance might lead to formation of more toxic metabolites accumulation in the body.
Polymorphisms (SNPs) in the genes coding for a particular enzyme can cause increase or decrease activity and both ways can be harmful.
The scientific evidence has been shown the association of impaired detoxification and certain diseases such as cancer, Parkinson’s disease, autoimmune conditions, autism, etc. The studies suggest that the liver detoxification enzyme system and the body’s ability to detoxify efficiently is impaired in many diseases.
“The human body is exposed to a wide array of xenobiotics in one’s lifetime, from food components to environmental toxins to pharmaceuticals, and has developed complex enzymatic mechanisms to detoxify these substances. These mechanisms exhibit significant individual variability, and are affected by environment, lifestyle, and genetic influences”. Liska, D. (1998)
Figure 2. Phase I and Phase II Liver Detoxification. Source [11]
Table 1. Phase I detoxification enzymes
Table 2. Phase II detoxification enzymes
N-acetyl transferase-2 (NAT2) liver detoxification enzyme
NAT2 gene polymorphisms can cause low or faster acetylation than normal acetylation. Both slow and rapid NAT2 acetylators are at increased risk for developing cancer if they are exposed to environmental toxins.
NAT2 fast acetylators vs NAT2 slow acetylators
NAT2 fast acetylators
NAT2 fast acetylators have an increased risk of heterocyclic amines created from smoking and from cooking meat in high temperatures such grilling. The individuals might have slow CYP1A2 enzyme (see table 1). NAT2 enzymes compete with CYP1A2 for substrates amines. Heterocyclic amines are found in tobacco smoke and are formed when meat is cooked at high temperatures.
A case control study nested within the Hawaii-Los Angeles Multi-ethnic Cohort Study found that cancer risk associated with smoking was greater among participants with NAT2 rapid acetylation compared to those with the slow/intermediate NAT2 genotype.
NAT2 fast acetylators have high risk for colon cancer and breast cancer. NAT2 fast acetylators have an increased risk of cancer when consuming well done cooked meat.
A study from Deitz AC et al. found that the breast cancer risk was increased among women with the rapid/intermediate NAT2 genotype and consumption of well-done meat. The breast cancer risk was increased nearly 8-fold compared with consuming rare or medium-done meats. These results support the hypothesis of high levels of heterocyclic amines exposure and the role for O-acetylation in the activation of heterocyclic amine carcinogens.
The studies have shown that the various preparation and cooking affect the formation of heterocyclic amines. The longer heating times of meat increases conversion of aminoacid creatine into creatinine. This increases the mutagenicity (ability to cause cancer cells) of the meat product.
Another factor that affects heterocyclic amines formation is presence of the reducing sugars (glucose, fructose, ribose, lactose). A significant reduction in mutagenicity was seen in grilled chicken that was marinated with honey (containing glucose and fructose in the same ratio and a small amount of sucrose). Oligosaccharides or inulin reduce the heterocyclic amines formation and decrease their mutagenicity in the body.
The heating time and heating temperatures (depending on the cooking methods) affect differently heterocyclic amines formation and their mutagenicity. A significant increase of heterocyclic amines concentration was already observed at 100 °C after 2 hours compared to a heating time of 1 hour. At 180, 200, and 220 °C, significant concentrations of heterocyclic amines were determined after 20 minutes.
The results of other studies have showed that heterocyclic amines formation depends on cooking methods. Adding substances such as antioxidants, nitrite or spices inhibits the heterocyclic amine formation and decreases the risk of cancer. Studies have shown that phenolic antioxidants, such as epigallocatechin gallate found in green tea, sesamol, extract of vegetables and fruits reduce the mutagenicity effect of heterocyclic amines. Sulfur compounds such as marination with garlic, onion and lemon juices inhibited the heterocyclic amines formation. The thiol in sulfur amino acids inhibits nonenzymatic browning of heated amino acid with glucose mixtures. Those compounds increase formation of glutathione and L-cysteine which both inhibit formation of cancer cells.
Garlic is an Allium genus plant and contains organic sulfur compounds such as allicin, diallyl disulfide and diallyl sulfide . Diallyl disulfide could inhibit heterocyclic amines formation. The sodium bisulfide in canned foods has been studied to demonstrate significant inhibition of formation of heterocyclic amines.
Many studies have demonstrated the effect of garlic in various types of cancer. Chung, JG (1999) has shown that higher concentration of diallyl disufide and diallyl sulfide found in garlic, the higher inhibition of NAT2 activity and cell death in human bladder tumour cell.
Begas et al. found that consuming twice daily intake of peppermint tea over 6 days decreased NAT2 activity.
NAT2 slow acetylators
NAT2 slow acetylators have low acetylation of aromatic amines (benzene, toluene, hair dye, primaquine, tenoxicam drug). The NAT2 slow acetylators with exposure to aromatic amines have higher risk of bladder cancer.
Wu, H. et al. study showed that the bladder cancer risk is significantly increased in NAT2 slow acetylation phenotypes compared with the rapid phenotypes.
NAT2 slow acetylators have high risk of hepatitis (liver inflammation) as side effect of treatment of Tuberculosis (TB) infection with Isoniazid (INH) drug.
A study from Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute in Poland has found an increase of INH blood level in NAT2 slow acetylators. The average INH blood level concentration was 2-to 7- fold higher in NAT2 slow acetylators.
Figure 3. Tuberculosis drug Isoniazid (INH) biotransformation in liver, NAT2 acetylation. Source [1]
Khan and Das (2020) have proposed an approach for treating TB in India based on NAT2 acetylator status. India is dealing with the most burden of TB and Mycobacterium Tuberculosis (MTB) drug resistance cases around the globe. Based on their proposal “while keeping the daily dose per kilo body weight to the same level for both the acetylation phenotypes”, patients with NAT2 slow acetylation phenotype can get INH in a lower concentration than the current dose; the NAT2 fast acetylators can get the effective concentration; in both cases with frequent repeats.
It is known in TB treatment that INH drug causes liver toxicity, and this depends on certain liver enzymes including NAT2. The scientists have discussed the importance of NAT2 slow acetylation not only causing side effects on liver toxicity, but as well it creates an environment for MTB and drug resistance. Finding the NAT2 acetylation phenotype for TB patients is seen as an effective and efficient treatment.
Another study from Rana et al (2013) suggests NAT2 phenotype and INH blood levels to be done before starting a safe and more suitable dose of INH in patients with tuberculosis. INH is metabolized by NAT2 and cytochrome P450 2E1(CYP2E1) and form hepatotoxins which is further metabolized by glutathione-S- transferase which removes the toxic metabolites.
It is metabolized by hepatic N-acetyltransferase-2 (NAT2) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins [4]. Glutathione-S-transferase is a phase-II drug-metabolizing enzyme, which is involved in detoxification of hepatotoxins.
Figure 4. NAT2 pathway in Isoniazid (INH) metabolism. Source [3]
NAT2 slow acetylators have a high adverse event from the drug sulfasalazine. NAT2 is a key enzyme for the acetylation of sulfasalazine. This drug is used in rheumatoid arthritis, psoriasis, and ulcerative colitis.
A study published in Canada Journal of Gastroenterology (2013) described that NAT2 slow acetylator genotype in Chinese population in the study was not associated with susceptibility to Inflammatory Bowel Disease (IBD); the sulphapyridine treatment of IBD was associated with dose-related adverse effects. Note: Sulphasalazine is a combination of sulphapyridine and 5-aminosalicylic acid.
NAT2 slow acetylator status have shown higher risk of drug related side effects such as lupus like syndrome from hydralazine (antihypertensive drug) or procainamide (anti arrhythmic drug).
NAT2 slow acetylators have higher risk of immunoglobulin E-mediated food allergy. A study published in Clinical Pharmacology and Therapeutics compared 136 children with food allergy, 23 healthy children, and their NAT2 acetylator status. None of the children with food allergy were NAT2 fast acetylators homozygos. The risk of developing immunoglobulin E-mediated food allergy was 3-fold greater in children with NAT2 slow acetylator status compared to healthy subjects.
Nacak and collegues have found increase risk of extrinsic asthma in patients NAT2 slow acetylators.
NAT2 helps breakdown of histamine. Histamine is a type of amine which is increased in acute inflammatory allergy responses and release of stomach acid. Histamine regulates sleep-wake cycle. Histamine is present in different foods. Foods high in histamine include aged cheese, fermented food and beverages, avocado, wine. Histamine is broken down from certain enzymes such as diaminoxidase (DAO) in the gut, histamine-n-methyltransferase (HNMT), NAT2 which converts histamine into acetylhistamine then secreted in urine. If the histamine breakdown is impaired and there is high consumption of food or beverages high in histamine, potentially increase the histamine levels in the body. High histamine causes histamine intolerance such as abdominal discomfort, headache, running nose, itching, hives, sleep issues.
Figure 5. Histamine pathway, DAO, HNMT, NAT2 enzymes. Source [16]
The good news is that foods that generally improve Phase I detoxification CYP SNPs improve Phase II detoxification. A diet high in fruits and vegetables improves the detoxification in general.
Charron and collegues have shown that kale diet increased CYP1A2 enzyme activity (Phase I liver detoxification enzyme) and decreased the conjugated biluribin. CYP1A2 activity was increased 16.4% and 15.2% on day 8 and 15 respectively. The conjugated biluribin was reduced by 54.5% by day 15. CYP1A2 enzyme is involved in metabolism of medical drugs, bioactivation of procancerous amines and aflatoxins.
The anticancer activity of brassica vegetables is associated generally with bioactive isothiocyanates and indoles. The indole-3-carbinol upregulates both Phase I liver detox enzymes such as CYP1A1 and CYP1A2, and as well Phase II liver detox enzymes. The isothiocyanates increase the acitivity of Phase II liver detox enzymes such as uridine diphosphate glucoronosyl (UGT) transferase (involved in bilurubin, environmental carcinogens and drugs metabolism), glutathione S-transferases (GST) and Nrf2.
Zhang and colleagues of the Johns Hopkins group were investigating chemoprevention in the early 1990s. They found that broccoli sprouts which are source of sulforaphane induced genes for coding enzymes of Phase II liver detoxification. Many studies have shown the benefits of Brassica family vegetables in liver detoxification and decrease of inflammation.
Figure 6. Phytochemical/ Nutrient induction of Phase II Liver Detox Enzyme Quinone Reductase.
Conclusion:
- NAT2 fast acetylators have an increased risk of cancer (especially colon and breast cancer) due to environmental exposures to heterocyclic amines created from smoking and cooked meat. It is important this individuals to reduce meat consuming and especially cooked in higher temperatures and for a longer time. Marination of meat with herbs and using plants that are source of sulfur compounds such as garlic, ginger, onion, broccoli (easy to remember GGOB) reduce the formation of heterocyclic amines and as a result decrease the risk of cancer.
- NAT2 slow acetylators have an increased risk of cancer, especially bladder cancer from environmental exposures to aromatic amines found in hair dye, benzene, toluene. These individuals that are under Tuberculosis treatment with medication Isoniazid, Sulfasalazine (for treatment of ulcerative colitis, psoriasis, rheumatoid arthritis) or Primaquine (treatment of malaria), have higher risk of side effects. It is recommended from some studies that NAT2 genetic polymorphism testing done prior the treatment will benefit public health, especially with long course treatment with tuberculosis medication Isoniazid to avoid treatment failure and prevent drug resistance.
- Consume daily a diet with plenty fruits and vegetables which provide phytochemicals to help detoxification. The most important vegetables with detox ability are cruciferous vegetables or Brassica family high in sulforaphane (broccoli, kale, Brussel sprouts, cabbage, cauliflower); high sulfur vegetables (GGOB: garlic, ginger, onion, broccoli, and other cruciferous vegetables); high phytonutrients found in berries and grapes, green and black tea; herbs and spices (turmeric, cumin, rosemary, basil, black pepper).
References
- Zabost et al. Correlation of N-Acetyltransferase 2 genotype with Isoniazid acetylation in Polish Tuberculosis patients. BioMed Research International. Dec 2013. https://doi.org/10.1155/2013/853602.
- Nikhat Khan & Aparup Das. Can the personalized medicine approach contribute in controlling tuberculosis in general and India in particular? Precision Clinical Medicine, Volume 3, Issue 3, September 2020, Pages 240–243, https://doi.org/10.1093/pcmedi/pbaa021.
- Rana et al. Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients. Hepatology International. August 2011. DOI: 10.1007/s12072-011-9309-4.
- Chen M et al. N-acetyltransferase 2 slow acetylator genotype associated with adverse effects of sulphasalazine in the treatment of inflammatory bowel disease. Canada J Gatsroenterol. 2007 Mar; 21 (3):155-8.
- Deitz AC et al. N-Acetyltransferase-2 genetic polymorphism, well-done meat intake, and breast cancer risk among postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2000 Sep;9(9):905-10. PMID: 11008907.
- Nöthlings, Ute et al. “Meat and heterocyclic amine intake, smoking, NAT1 and NAT2 polymorphisms, and colorectal cancer risk in the multi-ethnic cohort study.” Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology vol. 18,7 (2009): 2098-106. doi: 10.1158/1055-9965.EPI-08-1218.
- Gibis, Monica. Heterocyclic aromatic amines in cooked meat products causes, formation, occurrence, and risk assessment. Comprehensive reviews in Food Science and Food Safety. January 2016. https://doi.org/10.111/1541-4337.12186.
- Chung JG. Effects of garlic components diallyl sulfide and diallyl disulfide on arylamine N-acetyltransferase activity in human bladder tumor cells. Drug Chem Toxicol. 1999 May;22(2):343-58. doi: 10.3109/01480549909017839. PMID: 10234471.
- Wu H. et al. Association Between N-acetyltransferase 2 Polymorphism and Bladder Cancer Risk: Results from Studies of the Past Decade and a Meta-Analysis. Clin Genitourin Cancer. 2016 Apr;14(2):122-9. doi: 10.1016/j.clgc.2015.10.007. Epub 2015 Oct 26. PMID: 26585839.
- Houghton, C A. Sulforaphane: Its “Coming of Age” as a clinically relevant nutraceutical in the prevention and treatment of chronic disease”, Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 2716870, 27 pages 2019. https://goi.org/10.1155/2019/2716870.
- Liska, Deann. (1998). The Detoxification Enzyme System. Alternative medicine review : a journal of clinical therapeutic. 3. 187-98.
- Jung JA, et al. A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis. Drug Des Devel Ther. 2015;9:5433-5438 https://doi.org/10.2147/DDDT.S87131
- Kinzig-Schippers, M. et al. Should We Use N-Acetyltransferase Type 2 Genotyping To Personalize Isoniazid Doses? Antimicrobial Agents and Chemotherapy. Apr 2005, 49 (5) 1733-1738; DOI: 10.1128/AAC.49.5.1733-1738.2005
- Gawrońska-Szklarz, et al. Genotype of N-acetyltransferase 2 (NAT2) polymorphism in children with immunoglobulin E–mediated food allergy. Clinical Pharmacology and Therapeutics. 02 May 2001 https://doi.org/10.1067/mcp.2001.115541
- Nacak, M. et al. Association between the N-acetylation genetic polymorphism and bronchial asthma. Br J Clin Pharmacol. 2002;54(6):671-674. doi:10.1046/j.1365-2125.2002.01670.x.
- Lynch, B. Does SIBO Affect Histamine Intolerance and DAO? [Available from:https://www.drbenlynch.com/sibo-histamine/].
- Charron, J. Consumption of baby kale increased cytochrome P450 1A2 (CYP1A2) activity and influenced bilirubin metabolism in a randomized clinical trial. Journal of Functional Foods.Volume 64, 2020, 103624. ISSN 1756-4646. https://doi.org/10.1016/j.jff.2019.103624.
- Begas, E. Effects of peppermint tea consumption on the activities of CYP1A2, CYP2A6, Xanthine Oxidase, N-acetyltranferase-2 and UDP-glucuronosyltransferases-1A1/1A6 in healthy volunteers. Food and Chemical Toxicology, 100 (2017), pp. 80-89.
 and Clinical Significance in Cancer and Tuberculosis Treatment){kind=link}
0 Comments