Mar 06, 2024
UDP-GLUCURONOSYLTRANSFERASE (UGT)
UGT enzymes (uridine diphosphate-glucuronosyltransferase or UDP-glucuronosyltransferase) are a superfamily of enzymes that metabolize a wide variety of lipophilic molecules such as bilirubin, steroids, toxins, and drugs. These enzymes mediate the process of glucuronidation, a phase II metabolic pathway in which glucuronic acid is conjugated to specific targets, converting them into water-soluble metabolites that can then be excreted from the body (Hodges & Minich, 2015).
UGT genes are polymorphic (Guillemette et al., 2003), the UGT family is divided into 4 groups (Mackenzie et al., 2005). UGT1A, one of the members of the UGT family, is located on chromosome 2q37. It encodes more than one gene and pseudogene and has alternatively spliced isoforms (Van Es et al., 1993). Some of the variations in the UGT1A1 gene; They are UGT1A1 (rs6742078), UGT1A1*6 (rs4148323) and UGT1A1*60 (rs4124874).
Bilirubin, produced by the breakdown of heme, a component of hemoglobin, is a waste product. When old or damaged red blood cells are broken down in the spleen, hemoglobin is broken down into heme, which is then converted into bilirubin. The UGT1A1 enzyme converts this toxic, insoluble form of bilirubin (unconjugated bilirubin) into its non-toxic form (conjugated bilirubin). If bilirubin cannot be eliminated and accumulates at high levels, 'hyperbilirubinemia', also known as jaundice, occurs. This condition can cause a yellowish discoloration of the skin and eyes. Variants that reduce UGT1A1 enzyme activity can cause jaundice (Y.W. Francis Lam. et al., 2013; Barbarino et. al., 2014).
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Faz 2-UDP-glukuronosiltransferaz (UGT) |
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Genes |
rs kode |
Minor allele |
Minor Allele Description |
Reference |
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UGT1A1*60 |
rs4124874 |
C |
High relative risk for decreased enzyme activity and increased bilirubin |
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UGT1A1*6
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rs4148323 |
A |
Increased relative risk for hyperbilirubinemia. |
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UGT1A1 |
rs6742078 |
T |
Increased bilirubin and high relative risk for gallstones. |
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The table above contains UDP-glucuronosyltransferase (UGT) 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; The T/T allele of the UGT1A1 gene rs6742078 polymorphism was found to be associated with gallstone development (Buch et al., 2010). Another variant allele is UGT1A1*6. Homozygous individuals with this variant have decreased UGT1A1 enzyme activity, which can cause Gilbert syndrome and long-term neonatal jaundice (Maruo et al., 1999; Akaba et al., 1998). The A allele of the UGT1A1 gene rs4148323 polymorphism was found to be a protective factor for the development of hyper-free bilirubinemia in newborns (Hanafusa et al., 2022). The G allele of the UGT1A1 gene rs4124874 polymorphism was found to increase susceptibility to Neonatal Hyperbilirubinemia (Li et al., 2020). 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
Akaba K, Kimura T, Sasaki A, Tanabe S, Ikegami T, Hashimoto M, Umeda H, Yoshida H, Umetsu K, Chiba H, Yuasa I, Hayasaka K. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem Mol Biol Int. 1998 Sep;46(1):21-6. doi: 10.1080/15216549800203512. PMID: 9784835. https://pubmed.ncbi.nlm.nih.gov/9784835/
Barbarino, J. M., Haidar, C. E., Klein, T. E., & Altman, R. B. (2014). PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenetics and genomics, 24(3), 177–183. https://doi.org/10.1097/FPC.0000000000000024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091838/
Buch, S., Schafmayer, C., Völzke, H., Seeger, M., Miquel, J. F., Sookoian, S. C., Egberts, J. H., Arlt, A., Pirola, C. J., Lerch, M. M., John, U., Franke, A., von Kampen, O., Brosch, M., Nothnagel, M., Kratzer, W., Boehm, B. O., Bröring, D. C., Schreiber, S., Krawczak, M., & Hampe, J. (2010). Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. Gastroenterology, 139(6), 1942-1951.e1942. https://doi.org/10.1053/j.gastro.2010.09.003
Chapter 1 - Principles of Pharmacogenomics: Pharmacokinetic, Pharmacodynamic, and Clinical Implications., Y.W. Francis Lam, L.H.C.; [Cited March 2024]. Available from: https://www.sciencedirect.com/science/article/pii/B9780123919182000019
Fu, Z., Shrubsole, M. J., Li, G., Smalley, W. E., Hein, D. W., Cai, Q., Ness, R. M., & Zheng, W. (2013). Interaction of cigarette smoking and carcinogen-metabolizing polymorphisms in the risk of colorectal polyps. Carcinogenesis, 34(4), 779-786. https://doi.org/10.1093/carcin/bgs410
Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J. 2003;3(3):136-58. doi: 10.1038/sj.tpj.6500171. PMID: 12815363. https://pubmed.ncbi.nlm.nih.gov/12815363/
Hanafusa, H., Abe, S., Ohyama, S., Kyono, Y., Kido, T., Nakasone, R., Ashina, M., Tanimura, K., Nozu, K., & Fujioka, K. (2022). Influence of UGT1A1 Genetic Variants on Free Bilirubin Levels in Japanese Newborns: A Preliminary Study. International Journal of Environmental Research and Public Health, 19(20), 13090. https://www.mdpi.com/1660-4601/19/20/13090
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
Li, Z., Song, L., & Hao, L. (2020). The role of UGT1A1 (c.-3279 T > G) gene polymorphisms in neonatal hyperbilirubinemia susceptibility. BMC Medical Genetics, 21(1), 218. https://doi.org/10.1186/s12881-020-01155-2
Mackenzie PI, Bock KW, Burchell B, Guillemette C, Ikushiro S, Iyanagi T, Miners JO, Owens IS, Nebert DW. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics. 2005 Oct;15(10):677-85. doi: 10.1097/01.fpc.0000173483.13689.56. PMID: 16141793. https://pubmed.ncbi.nlm.nih.gov/16141793/
Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M. Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism. Pediatrics. 1999 Jun;103(6 Pt 1):1224-7. doi: 10.1542/peds.103.6.1224. PMID: 10353933. https://pubmed.ncbi.nlm.nih.gov/10353933/
Van Es HH, Bout A, Liu J, Anderson L, Duncan AM, Bosma P, Oude Elferink R, Jansen PL, Chowdhury JR, Schurr E. Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37. Cytogenet Cell Genet. 1993;63(2):114-6. doi: 10.1159/000133513. PMID: 8467709. https://pubmed.ncbi.nlm.nih.gov/8467709/