UDP glucuronosyltransferase 1 family, polypeptide A1

From Wikipedia, the free encyclopedia
Jump to: navigation, search
UDP glucuronosyltransferase 1 family, polypeptide A1
Identifiers
Symbols UGT1A1 ; BILIQTL1; GNT1; HUG-BR1; UDPGT; UDPGT 1-1; UGT1; UGT1A
External IDs OMIM191740 MGI98898 HomoloGene128034 ChEMBL: 1287617 GeneCards: UGT1A1 Gene
EC number 2.4.1.17
Orthologs
Species Human Mouse
Entrez 54658 394436
Ensembl ENSG00000241635 ENSMUSG00000089960
UniProt P22309 Q63886
RefSeq (mRNA) NM_000463 NM_201645
RefSeq (protein) NP_000454 NP_964007
Location (UCSC) Chr 2:
234.67 – 234.68 Mb
Chr 1:
88.21 – 88.22 Mb
PubMed search [1] [2]

UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.[1][2]

UGT-1A is a uridine diphosphate glucuronyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites.[3]

Gene[edit]

The UGT1A1 gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter.[3] 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[edit]

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:[4]

  • Gilbert syndrome (GS) can be caused by a variety of genetic changes, but in Caucasian and African-American populations, it is most commonly associated with the UGT1A1*28 allele (rs8175347), a homozygous 2-bp insertion (TA) mutation of the TATA box promoter region of the UGT1A1 gene.[4][5][6] This polymorphism impairs proper transcription of UGT1A1 gene, resulting in decreased transcriptional activity of UGT1A1 by about 70%; the resulting reduced enzyme activity leads to the hyperbilirubinemia characteristic of GS.[4][5][7] The *28 polymorphism occurs with a frequency of 26-31% in Caucasians and 42-56% of African-Americans.[8] About 10-15% of these populations are homozygous for the *28 allele, but only 5% actually develop UGT1A1-associated hyperbilirubinemia, so it appears that this mutation alone may be a necessary but not sufficient factor in GS, perhaps acting in combination with other UGT1A1 mutation(s) to increase the chances of developing GS.[4][5] In Asian and Pacific Islander populations, UGT1A1*28 is much less common, occurring at a frequency of approximately 9-16% in Asian populations and 4% of Pacific Islanders.[8][9] In these populations, Gilbert's syndrome is more often due to missense mutations in the coding region of the gene, such as UGT1A1*6 (glycine to arginine substitution at position 71 (G71R); rs4148323) [4][5] 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).[4][5]
  • 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.[4][10]
  • 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%.[4][11]
  • 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.[4][12]

Pharmacogenetics[edit]

Genetic variations within the UGT1A1 gene have also been associated with the development of certain drug toxicities. The UGT1A1*28 variant, the same allele behind many cases of Gilbert syndrome, has been associated with an increased risk for neutropenia in patients receiving the chemotherapeutic drug irinotecan. Specifically, patients homozygous for the *28 allele (i.e. those with the *28/*28 genotype) have an increased risk for developing neutropenia when treated with irinotecan, as compared to those with the UGT1A1*1/*1 or *1/*28 genotype.[13][14][15] However, some studies have found no link between the *28 allele and neutropenia.[16][17]

Since 2004, the U.S. Food and Drug Administration has recommended on the irinotecan drug label that patients with the *28/*28 genotype receive a lower starting dose of the drug. However, it is unclear whether this association is only relevant at medium or high doses of the drug. While some studies have found that the *28/*28 genotype is associated with an increased risk for neutropenia at all doses of irinotecan,[14] others have found a significant association only in patients taking medium (150 – 250 mg/m²) or high (≥250 mg/m²) doses.[15] The Dutch Pharmacogenetics Working Group recommends reducing irinotecan dose by 30% in patients with the *28/*28 genotype, but only if the dose is greater than 250 mg/m².[18][19]

The *28 allele has also been associated with an increased risk for developing diarrhea in patients receiving irinotecan, but results from individual studies have been mixed.[13][17][20][20][21] However, a meta-analysis with 1760 patients across 20 studies found that patients taking medium or high doses of irinotecan with either the *28/*28 or *1/*28 genotype had a significantly greater risk for experiencing severe diarrhea as compared to those with the *1/*1 genotype. No associations were found in patients taking a low (< 150 mg/m²) dose of irinotecan.[14]

The UGT1A1*6 variant, more common in Asian populations than the *28 variant, has also shown associations with the development of irinotecan toxicities. Patients who are heterozygous or homozygous for the *6 allele have a higher risk for developing neutropenia and diarrhea as compared to those with the UGT1A1*1/*1 genotype.[22][23][24]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:
IrinotecanPathway_WP46359 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article Go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article Go to article go to article
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
IrinotecanPathway_WP46359 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article Go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article Go to article go to article
|{{{bSize}}}px|class=noresize]]
Irinotecan Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP46359". 

See also[edit]

References[edit]

  1. ^ Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Bélanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW (August 1997). "The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence". Pharmacogenetics 7 (4): 255–69. doi:10.1097/00008571-199708000-00001. PMID 9295054. 
  2. ^ Strassburg CP, Manns MP, Tukey RH (April 1998). "Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8". J. Biol. Chem. 273 (15): 8719–26. doi:10.1074/jbc.273.15.8719. PMID 9535849. 
  3. ^ a b "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1". 
  4. ^ a b c d e f g h i Online 'Mendelian Inheritance in Man' (OMIM) UDP-glycosyltransferase 1 family, polypeptide A1; UGT1A1 -191740
  5. ^ a b c d e Online 'Mendelian Inheritance in Man' (OMIM) Gilbert syndrome -143500
  6. ^ Beutler E, Gelbart T, Demina A (July 1998). "Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?". Proc Natl Acad Sci USA 95 (14): 8170–4. doi:10.1073/pnas.95.14.8170. PMC 20948. PMID 9653159. 
  7. ^ Tukey RH, Strassburg CP, Mackenzie PI. (September 2002). "Pharmacogenomics of human UDP-glucuronosyltransferases and irinotecan toxicity". Mol Pharmacol 62 (3): 446–50. doi:10.1124/mol.62.3.446. PMID 12181419. 
  8. ^ a b Barbarino JM, Haidar CE, Klein TE, Altman RB (March 2014). "PharmGKB summary: very important pharmacogene information for UGT1A1". Pharmacogenet Genomics 24 (3): 177–83. doi:10.1097/FPC.0000000000000024. PMC 4091838. PMID 24492252. 
  9. ^ Al Fadhli S, Al-Jafer H, Hadi M, Al-Mutairi M, Nizam R. (October 2013). "The effect of UGT1A1 promoter polymorphism in the development of hyperbilirubinemia and cholelithiasis in hemoglobinopathy patients.". PLOS ONE 8 (10): e77681. doi:10.1371/journal.pone.0077681. PMC 3813713. PMID 24204915. 
  10. ^ Online 'Mendelian Inheritance in Man' (OMIM) Crigler-Najjar syndrome, type I -218800
  11. ^ Online 'Mendelian Inheritance in Man' (OMIM) Crigler-Najjar syndrome, type II -606785
  12. ^ Online 'Mendelian Inheritance in Man' (OMIM) Hyperbilirubinemia, transient familial neonatal -237900
  13. ^ a b Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ (April 2004). "Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan". J Clin Oncol 22 (8): 1382–8. doi:10.1200/jco.2004.07.173. PMID 15007088. 
  14. ^ a b c Hu ZY, Yu Q, Pei Q, Guo C (August 2010). "Dose-dependent association between UGT1A1*28 genotype and irinotecan-induced neutropenia: low doses also increase risk". Clin Cancer Res 16 (15): 3832–42. doi:10.1158/1078-0432.ccr-10-1122. PMID 20562211. 
  15. ^ a b Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL (September 2007). "UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters". J Natl Cancer Inst 99 (17): 1290–5. doi:10.1093/jnci/djm115. PMID 17728214. 
  16. ^ Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P, Rogatko A, Wang H, Blanchard RL (February 2005). "UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan". Clin Cancer Res 11 (3): 1226–36. PMID 15709193. 
  17. ^ a b Marcuello E, Altes A, Menoyo A, Del Rio E, Gomez-Pardo M, Baiget M (August 2004). "UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer". Br J Cancer 91 (4): 678–82. doi:10.1038/sj.bjc.6602042. PMC 2364770. PMID 15280927. 
  18. ^ http://www.pharmgkb.org/guideline/PA166104951
  19. ^ Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ (May 2011). "Pharmacogenetics: from bench to byte—an update of guidelines". Clin Pharmacol Ther 89 (5): 662–73. doi:10.1038/clpt.2011.34. PMID 21412232. 
  20. ^ a b Stewart CF, Panetta JC, O'Shaughnessy MA, Throm SL, Fraga CH, Owens T, Liu T, Billups C, Rodriguez-Galindo C, Gajjar A, Furman WL, McGregor LM. (June 2007). "UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan". J Clin Oncol 25 (18): 2594–600. doi:10.1200/jco.2006.10.2301. PMID 17577039. 
  21. ^ Massacesi C, Terrazzino S, Marcucci F, Rocchi MB, Lippe P, Bisonni R, Lombardo M, Pilone A, Mattioli R,Leon A. (March 2006). "Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy". Cancer 106 (5): 1007–16. doi:10.1002/cncr.21722. PMID 16456808. 
  22. ^ Onoue M, Terada T, Kobayashi M, Katsura T, Matsumoto S, Yanagihara K, Nishimura T, Kanai M, Teramukai S, Shimizu A, Fukushima M, Inui K. (April 2009). "UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients". Int J Clin Oncol 14 (2): 136–42. doi:10.1007/s10147-008-0821-z. PMID 19390945. 
  23. ^ Takano M, Kato M, Yoshikawa T, Sasaki N, Hirata J, Furuya K, Takahashi M, Yokota H, Kino N, Horie K,Goto T, Fujiwara K, Ishii K, Kikuchi Y, Kita T (March 2009). "Clinical significance of UDP-glucuronosyltransferase 1A1*6 for toxicities for combination chemotherapy with irinotecan and cisplatin in gynecologic cancers: a prospective multi-institutional study". Oncology 76 (5): 315–21. doi:10.1159/000209335. PMID 19299905. 
  24. ^ Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, Goh BC, Chowbay B (September 2007). "Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients". Cancer Sci 98 (9): 1461–7. doi:10.1111/j.1349-7006.2007.00541.x. PMID 17627617. 

External links[edit]

Further reading[edit]