Mar 06, 2024
What is detoxification?
The liver is a center where physiological and biochemical events occur in our body. Among all these functions, the most important function of the liver is detoxification (Sheriock, 2011). The liver carries out detoxification processes with enzymes. These enzymes transform toxic chemicals into water-soluble substances, and the products resulting from this transformation are excreted from the body with bile and urea as the end product (Liska, 1998; Sheriock, 2011).
Detoxification consists of 2 main stages: phase 1 and phase 2. In Phase 1 of the detoxification process, the liver converts toxic substances into intermediate metabolites that are more toxic than the original. In Phase 2, the second stage of detoxification, these more toxic intermediate metabolites are converted into more harmless and water-soluble substances by using enzymes to be excreted with bile or urea (Liska, 1998).
Detoxification Phase 1 Enzymes and Genes
Phase I generally constitutes the first enzymatic defense system against toxins. As a result of this stage in detoxification, reactive molecules that may be more toxic than the first molecule are produced (Vermeulen, 1996). In phase 1, oxidation, reduction and hydrolysis reactions occur by various enzyme classes (Grant, 1991).
Detoxification Phase 2 Enzymes and Genes
In Phase 2; Conjugation reactions such as glutathione conjugation, glucuronidation, methylation, acetylation, sulfation and amino acid conjugation occur (Apte, 2011). Generally, in conjugation reactions, substrates are converted into a more water-soluble and less toxic product (Parkinson, 2008).
Glutathione-S-Transferase (GST)
Glutathione-S-Transferase (GST) enzymes conjugate substrates with glutathione. Glutathione is very important in protecting cells from oxidative stress and removing toxic and carcinogenic substances from the body, and is the most important antioxidant for neutralizing free radicals produced in Phase 1. Since glutathione is also used in Phase 2 detoxification processes, it can be depleted during high toxic exposure. When depleted (when Phase 2 processes are forced to stop) oxidative stress increases in the body, which can lead to liver damage. The presence of polymorphism in the gene of this enzyme reveals differences in the excretion of these toxins (Hodges & Minich, 2015). The GST enzyme family consists of various classes, mainly alpha (A), pi (P), theta (T) and mu (M) (Hayes, 1995).
What is the GSTP1 gene?
GSTP1 is the most abundant protein subtype in the glutathione S transferase family. GSTP1 can reduce the damage of intracellular biological macromolecules by catalyzing the combination of glutathione (GSH) with various electrophilic and hydrophobic substances to form water-soluble compounds to be excreted from the body. Recent studies show that GSTP1 plays a vital role in maintaining cell oxidation balance and regulating cell proliferation and apoptosis (Lei et al., 2021).
What is the GSTM1 Gene?
As a result of genetic polymorphisms in GSTM1, GSTM1-null genotypes that lack GSTM1 enzymes are formed. The probability of these null genotypes varies according to ethnic groups (Rebbeck, 1997; Hayes, 1995). The frequency of GTSM1*0 individuals is approximately 67% in Australians, 50% in Caucasians and 22% in Nigerians. The GSTM null phenotype is associated with an increased risk of lung, colon, and bladder cancer (McIlwain et al., 2006). Individuals with the GSTM1 null genotype have a reduced capacity to detoxify some carcinogens, such as N-nitroso compounds that cause gastric carcinogenesis (Van Iersel, 1999).
What is the GSTA1 gene?
The GST α isoform is expressed mainly in the liver and is encoded by a gene cluster localized on chromosome 6p12. While human tissues widely express transcripts for GSTA1, A2, and A4, expression of GSTA3 is rare and GSTA5 has not yet been detected in human tissues. Epidemiological results indicate that abnormal expression of GSTα is associated with an increased risk of colorectal cancer, ovarian cancer, and clear cell renal cell carcinoma (McIlwain et al., 2006).
|
Phase II-Glutathione-S-Transferase (GST) |
||||
|
Genes |
rs-code |
Minor Allele |
Minor Allele Description |
Reference |
|
GSTP1 |
rs1695 |
G |
High relative risk for reduced enzyme function |
|
|
GSTM1 |
rs366631 |
T |
High relative risk for reduced GSTM1 activity. |
|
|
GSTA1 |
rs3957357 |
A |
High relative risk for allergies and asthma due to low or dysfunctional enzyme activity |
|
The table above contains Glutathione-S-transferase genes and polymorphisms. These polymorphisms are genetic variants that may predispose a person to certain conditions or protect a person against certain conditions. Studies on these genes are as follows; It has been found that the rs1695 G allele of the GSTP1 gene has a high risk of developing asthma (Mukhammadiyeva et al., 2022). Likewise, the GSTM1 rs 366631 T/T allele increased the risk of developing asthma disease (Su et al., 2020). Another study found that the T allele of the GSTA1 gene rs3957357 polymorphism was associated with a significantly increased risk of asthma (Piacentini et al., 2014). This shows us that the genetic polymorphisms people have may create a predisposition to diseases. Therefore, people can predict and prevent these risks by having genetic testing. They can prevent them from getting sick by regulating their lifestyle.
REFERENCES
Apte, U., Krishnamurthy, P. (2011). Detoxification Functions of the Liver. In: Monga, S. (eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_11
Grant, D. M. (1991). Detoxification Pathways in the Liver. In R. A. Harkness, R. J. Pollitt, & G. M. Addison (Eds.), Journal of Inherited Metabolic Disease (pp. 421-430). Springer Netherlands. https://doi.org/10.1007/978-94-011-9749-6_2
Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30(6):445-600. doi: 10.3109/10409239509083491. PMID: 8770536. https://www.tandfonline.com/doi/abs/10.3109/10409239509083491
Hodges, R. E., & Minich, D. M. (2015). Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. Journal of Nutrition and Metabolism, 2015, 760689. https://doi.org/10.1155/2015/760689
Lei, X., Du, L., Yu, W., Wang, Y., Ma, N., & Qu, B. (2021). GSTP1 as a novel target in radiation induced lung injury. Journal of Translational Medicine, 19. https://doi.org/10.1186/s12967-021-02978-0
Liska, D. J. (1998). The detoxification enzyme systems. Altern. Med. Rev, 187-198.
McIlwain, C., Townsend, D., & Tew, K. (2006). Glutathione S-transferase polymorphisms: Cancer incidence and therapy. Oncogene, 25(11), 1639. https://doi.org/10.1038/sj.onc.1209373
Mukhammadiyeva, G. F., Bakirov, A. B., Karimov, D. O., Ziatdinova, M. M., Valova, Y. V., Borisova, A. I., & Distanova, A. A. (2022). Analysis of the GSTP1 rs1695 polymorphism association with the development of asthma and phenotypic manifestations. Journal of Asthma, 59(6), 1065-1069. https://doi.org/10.1080/02770903.2021.1910295
Parkinson, A., & Ogilvie, B. W. (2008). Biotransformation of xenobiotics. Casarett and Doull’s toxicology: the basic science of poisons, 7, 161-304. https://accesspharmacy.mhmedical.com/Content.aspx?bookId=958§ionId=53483726
Piacentini, S., Polimanti, R., Iorio, A., Cortesi, M., Papa, F., Rongioletti, M., Liumbruno, G. M., Manfellotto, D., & Fuciarelli, M. (2014). GSTA1*-69C/T and GSTO2*N142D as asthma- and allergy-related risk factors in Italian adult patients. Clinical and Experimental Pharmacology and Physiology, 41(3), 180-184. https://doi.org/https://doi.org/10.1111/1440-1681.12201
Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1997 Sep;6(9):733-43. PMID: 9298582. https://pubmed.ncbi.nlm.nih.gov/9298582/
Sheriock, S. (2011). Diseases of the liver and biliary system. Blockwell Scientific Publications. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954253/
Su, X., Ren, Y., Li, M., Kong, L., & Kang, J. (2020). Association of glutathione S-transferase M1 and T1 genotypes with asthma: A meta-analysis. Medicine, 99(34). https://journals.lww.com/md-journal/Fulltext/2020/08210/Association_of_glutathione_S_transferase_M1_and_T1.47.aspx
Van Iersel ML, Verhagen H, van Bladeren PJ. The role of biotransformation in dietary (anti)carcinogenesis. Mutat Res. 1999 Jul 15;443(1-2):259-70. doi: 10.1016/s1383-5742(99)00023-x. PMID: 10415444. https://pubmed.ncbi.nlm.nih.gov/10415444/
Vermeulen, N. P. E. (1996). Role of Metabolism in Chemical Toxicity, In:Ioannides, C.,ed., CytP450: Metabolic and Toxicological Aspects, BocaRaton. CRC press, Inc, 29-53. https://books.google.com.tr/books?hl=en&lr=&id=m1W6jfvi7YcC&oi=fnd&pg=PA29&dq=info:GopEHmat2_AJ:scholar.google.com&ots=wpa4mwRB9x&sig=qXy1qj3jv0BEFVxU6cDEQgGVumk&redir_esc=y#v=onepage&q&f=false