UDP glucuronosyltransferase 1 family, polypeptide A1
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| Location (UCSC) | Chr 2: 233.76 – 233.77 Mb | Chr 1: 88.14 – 88.15 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.[5][6]
UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pathway that transforms small lipophilic (fat-soluble) molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites.[7]
Gene
The UGT1A1 gene is part of a complex
promoter.[7] Over 100 genetic variants within the UGT1A1 gene have been described, some of which confer increased, reduced or inactive enzymatic activity. The UGT nomenclature committee
has compiled a list of these variants, naming each with a * symbol followed by a number.
Clinical significance
Mutations in this gene cause serious problems for bilirubin metabolism; each syndrome can be caused by one or many mutations, so they are differentiated mostly by symptoms and not particular mutations:[8]
- missense mutations in the coding region of the gene, such as UGT1A1*6 (glycine to arginine substitution at position 71 (G71R); rs4148323) [8][9] A special phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3) helps to increase UDPGT enzyme production, which would make it conceptually possible to medically control the bilirubin level, although this is rarely necessary, particularly in adults (usually the level of total serum bilirubin in Gilbert syndrome patients vary from 1 to 6 mg/dL).[8][9]
- Crigler–Najjar syndrome, type I is associated with mutation(s) that result in a complete absence of normal UGT1A1 enzyme, which causes a severe hyperbilirubinemia with levels of total serum bilirubin from 20 to 45 mg/dL. Phenobarbital treatment does not help to lower bilirubin level, because it only increases the amount of mutated UGT1A1 enzyme, which is still unable to catalyze the glucuronidation of bilirubin, which on the other hand makes phenobarbital treatment diagnostically relevant.[8][14]
- Crigler–Najjar syndrome, type II is associated with other mutation(s) that lead to a reduced activity of the mutated UGT1A1 enzyme, which causes a hyperbilirubinemia with levels of total serum bilirubin from 6 to 20 mg/dL. In this case phenobarbital treatment helps to lower bilirubin lever by more than 30%.[8][15]
- Hyperbilirubinemia, familial transient neonatal (also called breastfeeding jaundice) is associated with mutation(s) that alone do not lead to bilirubin level increase in female patients, but their children when breastfed develop from mild to severe hyperbilirubinemia by receiving steroidal substances (with milk) inhibiting glucuronidation of unconjugated bilirubin that may lead to jaundice and even kernicterus.[8][16]
Pharmacogenetics
Genetic variations within the UGT1A1 gene have also been associated with the development of certain
homozygous for the *6 allele may have a higher risk for developing neutropenia and diarrhea as compared to those with the UGT1A1*1/*1 genotype.[17][18]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Irinotecan Pathway edit
- ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".
See also
- Glucuronosyltransferase
- Lucey-Driscoll syndrome
- Neonatal jaundice
- Cancer pharmacogenomics
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000241635 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000089960 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9295054.
- PMID 9535849.
- ^ a b "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1".
- ^ a b c d e f g h i Online Mendelian Inheritance in Man (OMIM): UDP-glycosyltransferase 1 family, polypeptide A1; UGT1A1 - 191740
- ^ a b c d e Online Mendelian Inheritance in Man (OMIM): Gilbert syndrome - 143500
- PMID 9653159.
- S2CID 19666863.
- ^ PMID 24492252.
- PMID 24204915.
- ^ Online Mendelian Inheritance in Man (OMIM): Crigler–Najjar syndrome, type I - 218800
- ^ Online Mendelian Inheritance in Man (OMIM): Crigler–Najjar syndrome, type II - 606785
- ^ Online Mendelian Inheritance in Man (OMIM): Hyperbilirubinemia, transient familial neonatal - 237900
- ^ PMID 20602618.
- ^ PMID 24492252.
- ^ PMID 31633039.
- ^ "CAMPTOSAR (irinotecan hydrochloride injection, solution) drug label". DailyMed. U.S. National Library of Medicine. Retrieved 5 January 2015.
Further reading
- Tukey RH, Strassburg CP (2000). "Human UDP-glucuronosyltransferases: metabolism, expression, and disease". Annu. Rev. Pharmacol. Toxicol. 40: 581–616. PMID 10836148.
- Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR (2000). "Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype". Hum. Mutat. 16 (4): 297–306. S2CID 24275067.
- King CD, Rios GR, Green MD, Tephly TR (2001). "UDP-glucuronosyltransferases". Curr. Drug Metab. 1 (2): 143–61. PMID 11465080.
- Bosma PJ (2003). "Inherited disorders of bilirubin metabolism". J. Hepatol. 38 (1): 107–17. PMID 12480568.
- Innocenti F, Ratain MJ (2003). "Irinotecan treatment in cancer patients with UGT1A1 polymorphisms". Oncology (Williston Park, N.Y.). 17 (5 Suppl 5): 52–5. PMID 12800608.
- Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development". Oncologist. 10 (2): 104–11. PMID 15709212.
- Navarro SL, Peterson S, Chen C, Makar KW, Schwarz Y, King IB, Li SS, Li L, Kestin M, Lampe JW (2009). "Cruciferous vegetable feeding alters UGT1A1 activity: diet and genotype-dependent changes in serum bilirubin in a controlled trial". Cancer Prev. Res. 2 (4): 345–52. PMID 19336732.
- Barbarino JM, Haidar CE, Klein TE, Altman RB (March 2014). "PharmGKB summary: very important pharmacogene information for UGT1A1". Pharmacogenet Genomics. 24 (3): 177–83. PMID 24492252.
External links
- UGT1A1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- UGT nomenclature homepage
- PharmGKB page for UGT1A1
