bilirubin glucuronide

{{Short description|Chemical compound}}

{{Chembox

| ImageFile = Bilirubin glucuronide.svg

| ImageSize = 250px

| IUPACName = 3-[12-(2-Carboxyethyl)-3,18-diethenyl-2,7,13,17-tetramethyl-1,19-dioxo-10,19,21,22,23,24-hexahydro-1H-bilin-8-yl]propanoyl β-D-glucopyranosiduronic acid

| SystematicName = [1²(2)Z,10²S,10³R,10⁴S,10⁵S,10⁶S]-3⁴-(2-Carboxyethyl)-1⁴-ethenyl-5⁵-[(Z)-(3-ethenyl-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)methyl]-10³,10⁴,10⁵-trihydroxy-1³,3³,5⁴-trimethyl-1⁵,8-dioxo-1¹,1⁵-dihydro-3¹H,5¹H-9-oxa-1(2),3(2,5),5(2,3)-tripyrrola-10(2)-oxanadecaphan-1²(2)-ene-10⁶-carboxylic acid

| OtherNames = Bilirubin monoglucuronide

|Section1={{Chembox Identifiers

| CASNo = 27071-67-6

| KEGG = C03374

| PubChem = 5280588

| ChEMBL = 2074720

| ChEBI = 16427

| ChemSpiderID = 4444203

| StdInChI = 1S/C39H44N4O12/c1-7-20-19(6)36(50)43-27(20)14-25-18(5)23(10-12-31(46)54-39-34(49)32(47)33(48)35(55-39)38(52)53)29(41-25)15-28-22(9-11-30(44)45)17(4)24(40-28)13-26-16(3)21(8-2)37(51)42-26/h7-8,13-14,32-35,39-41,47-49H,1-2,9-12,15H2,3-6H3,(H,42,51)(H,43,50)(H,44,45)(H,52,53)/b26-13-,27-14-/t32-,33-,34+,35-,39+/m0/s1

| StdInChIKey = ARBDURHEPGRPSR-LCNKTQGVSA-N

| SMILES = CC1=C(NC(=C1CCC(=O)O)CC2=C(C(=C(N2)/C=C\3/C(=C(C(=O)N3)C)C=C)C)CCC(=O)O[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)C(=O)O)O)O)O)/C=C\5/C(=C(C(=O)N5)C=C)C

}}

|Section2={{Chembox Properties

|C=39|H=44|N=4|O=12

}}

}}

Bilirubin glucuronide is a water-soluble reaction intermediate over the process of conjugation of indirect bilirubin.{{cite book | last1=Divers | first1=Thomas J. | last2=Barton | first2=Michelle Henry | title=Equine Internal Medicine | chapter=Disorders of the Liver | publisher=Elsevier | year=2018 | isbn=978-0-323-44329-6 | doi=10.1016/b978-0-323-44329-6.00013-9 | pages=843–887 | quote= then convert biliverdin to bilirubin and release it from the cell as free, insoluble bilirubin. This form of bilirubin also is referred to as indirect-reacting or unconjugated bilirubin.}} Bilirubin glucuronide itself belongs to the category of conjugated bilirubin along with bilirubin di-glucuronide. However, only the latter one is primarily excreted into the bile in the normal setting.[https://web.archive.org/web/20190506100020/https://library.med.utah.edu/NetBiochem/images/decsec.gif Dubin-Johnson syndrome is associated with inability of the hepatocytes to secrete conjugated bilirubin after it has been formed.]{{cite journal | last1=Nishida | first1=T | last2=Gatmaitan | first2=Z | last3=Roy-Chowdhry | first3=J | last4=Arias | first4=I M | title=Two distinct mechanisms for bilirubin glucuronide transport by rat bile canalicular membrane vesicles. Demonstration of defective ATP-dependent transport in rats (TR-) with inherited conjugated hyperbilirubinemia. | journal=Journal of Clinical Investigation | publisher=American Society for Clinical Investigation | volume=90 | issue=5 | date=1992-11-01 | issn=0021-9738 | pmid=1430236 | pmc=443282 | doi=10.1172/jci116098 | pages=2130–2135}}{{cite journal | last1=Zhou | first1=J. | last2=Tracy | first2=T. S. | last3=Remmel | first3=R. P. | title=Bilirubin Glucuronidation Revisited: Proper Assay Conditions to Estimate Enzyme Kinetics with Recombinant UGT1A1 | journal=Drug Metabolism and Disposition | volume=38 | issue=11 | date=2010-07-28 | issn=0090-9556 | pmid=20668247 | pmc=2967393 | doi=10.1124/dmd.110.033829 | pages=1907–1911}}

Upon macrophages spot and phagocytize the effete Red Blood Corpuscles containing hemoglobin,{{cite journal | last1=Berk | first1=Paul D. | last2=Howe | first2=Robert B. | last3=Bloomer | first3=Joseph R. | last4=Berlin | first4=Nathaniel I. | title=Studies of bilirubin kinetics in normal adults | journal=The Journal of Clinical Investigation | volume=48 | issue=11 | date=1969-11-01 | issn=0021-9738 | pmid=5824077 | pmc=297471 | doi=10.1172/jci106184 | pages=2176–2190}} unconjugated bilirubin is discharged from macrophages into the blood plasma.{{cite web | title=Heme metabolism in macrophages | website=eClinpath | url=http://eclinpath.com/chemistry/iron-metabolism/heme-metabolism/ | access-date=2019-05-05 | archive-url=https://web.archive.org/web/20180517180004/http://www.eclinpath.com/chemistry/iron-metabolism/heme-metabolism/ | archive-date=2018-05-17 | url-status=live }}{{cite web | title=Bilirubin and hemolytic anemia | website=eClinpath | url=http://eclinpath.com/chemistry/liver/cholestasis/bilirubin/bilirubin-and-hemolysis/ | access-date=2019-05-05 | archive-url=https://web.archive.org/web/20180807065737/http://www.eclinpath.com/chemistry/liver/cholestasis/bilirubin/bilirubin-and-hemolysis/ | archive-date=2018-08-07 | url-status=live }} Most often, the free and water-insoluble unconjugated bilirubin which has an internal hydrodren{{Clarify|reason=hydrodren, or hydrogen !?|date=February 2024}} bonding{{cite web | title=Bilirubin metabolism | website=UpToDate | url=https://www.uptodate.com/contents/bilirubin-metabolism | access-date=2019-05-05 | author1=Namita Roy-Chowdhury |author2=Jayanta Roy-Chowdhury | editor1=Sanjiv Chopra |editor2=Elizabeth B Rand | editor3=Shilpa Grover | archive-url=https://web.archive.org/web/20171024195633/http://www.uptodate.com/contents/bilirubin-metabolism | archive-date=2017-10-24 | url-status=live }} will bind to albumin and, to a much lesser extent, high density lipoprotein in order to decrease its hydrophobicity and to limit the probability of unnecessary contact with other tissues and keep bilirubin in the vascular space from traversing to extravascular space including brain, and from ending up increasing glomerular filtration. Nevertheless, there is still a little portion of indirect bilirubins stays free-of-bound. Free unconjugated bilirubin can poison the cerebrum.{{cite journal | title=Definition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND) | issue=1 | pages=54–59 | journal=Journal of Perinatology | volume=25 | doi=10.1038/sj.jp.7211157 | pmid=15578034 | date=January 2005 | last1=Shapiro | first1=Steven M. | s2cid=19663259 }}{{cite journal | last=Brites | first=Dora | title=The Evolving Landscape of Neurotoxicity by Unconjugated Bilirubin: Role of Glial Cells and Inflammation | journal=Frontiers in Pharmacology | volume=3 | pages=88 | date=2012-05-29 | issn=1663-9812 | pmid=22661946 | pmc=3361682 | doi=10.3389/fphar.2012.00088 | doi-access=free }}{{cite journal | last1=Wusthoff | first1=Courtney J. | last2=Loe | first2=Irene M. | title=Impact of bilirubin-induced neurologic dysfunction on neurodevelopmental outcomes | journal=Seminars in Fetal & Neonatal Medicine | volume=20 | issue=1 | date=2015-01-10 | issn=1744-165X | pmid=25585889 | pmc=4651619 | doi=10.1016/j.siny.2014.12.003 | pages=52–57}}{{cite journal | last1=Radmacher | first1=Paula G | last2=Groves | first2=Frank D | last3=Owa | first3=Joshua A | last4=Ofovwe | first4=Gabriel E | last5=Amuabunos | first5=Emmanuel A | last6=Olusanya | first6=Bolajoko O | last7=Slusher | first7=Tina M | title=A modified Bilirubin-induced neurologic dysfunction (BIND-M) algorithm is useful in evaluating severity of jaundice in a resource-limited setting | journal=BMC Pediatrics | volume=15 | issue=1 | pages=28 | date=2015-04-01 | issn=1471-2431 | doi=10.1186/s12887-015-0355-2 | pmid=25884571 | pmc=4389967 | doi-access=free }}{{cite journal | last1=Johnson | first1=Lois | last2=Bhutani | first2=Vinod K. | title=The Clinical Syndrome of Bilirubin-Induced Neurologic Dysfunction | journal=Seminars in Perinatology | volume=35 | issue=3 | year=2011 | issn=0146-0005 | doi=10.1053/j.semperi.2011.02.003 | pmid=21641482 | pages=101–113}}{{cite journal | last1=Bhutani | first1=Vinod K. | last2=Wong | first2=Ronald | title=Bilirubin-induced neurologic dysfunction (BIND) | journal=Seminars in Fetal and Neonatal Medicine | volume=20 | issue=1 | year=2015 | issn=1744-165X | doi=10.1016/j.siny.2014.12.010 | pmid=25577656 | page=1}}{{cite journal | last=Press | first=Dove | title=Acute bilirubin encephalopathy and its progression to kernicterus: cur - RRN | journal=Research and Reports in Neonatology | volume=8 | date=2018-03-07 | doi=10.2147/RRN.S125758 | pages=33–44 | url=https://www.dovepress.com/acute-bilirubin-encephalopathy-and-its-progression-to-kernicterus-curr-peer-reviewed-fulltext-article-RRN | access-date=2019-05-06 | archive-url=https://web.archive.org/web/20190506035641/https://www.dovepress.com/acute-bilirubin-encephalopathy-and-its-progression-to-kernicterus-curr-peer-reviewed-fulltext-article-RRN | archive-date=2019-05-06 | url-status=live | doi-access=free }}{{cite book | last1=Smith | first1=Margaret E. | last2=Morton | first2=Dion G. | title=The Digestive System | chapter=Liver and Biliary System | publisher=Elsevier | year=2010 | isbn=978-0-7020-3367-4 | doi=10.1016/b978-0-7020-3367-4.00006-2 | pages=[https://archive.org/details/digestivesystemb0000smit/page/85 85–105] | quote=However, when jaundice is present it is likely that many other potentially toxic materials have also accumulated in the blood as a consequence of their reflux from the bile or impaired secretion from the hepatocyte. This can lead to impaired mental function and malaise. | chapter-url=https://archive.org/details/digestivesystemb0000smit/page/85 }}{{cite journal|author2-link=Claudio Tiribelli | last1=Watchko | first1=Jon F. | last2=Tiribelli | first2=Claudio | editor-last=Ingelfinger | editor-first=Julie R. | title=Bilirubin-Induced Neurologic Damage — Mechanisms and Management Approaches | journal=The New England Journal of Medicine | volume=369 | issue=21 | date=2013-11-21 | issn=0028-4793 | pmid=24256380 | doi=10.1056/nejmra1308124 | pages=2021–2030}}{{cite journal | last1=Shapiro | first1=Steven M. | last2=Bhutani | first2=Vinod K. | last3=Johnson | first3=Lois | title=Hyperbilirubinemia and Kernicterus | journal=Clinics in Perinatology | volume=33 | issue=2 | year=2006 | issn=0095-5108 | pmid=16765731 | doi=10.1016/j.clp.2006.03.010 | pages=387–410}}

Finally, albumin leads the indirect bilirubin to the liver. In the liver sinusoid, albumin disassociates with the indirect bilirubin and returns to the circulation while the hepatocyte transfers the indirect bilirubin to ligandin and glucuronide conjugates the indirect bilirubin in the endoplasmic reticulum by disrupting unconjugated bilirubin's internal hydrogen bonding, which is the thing that makes indirect bilirubin having the property of eternal half-elimination life and insoluble in water,Structure of bilirubin Bonnet RJ, Davis E, Hursthouse MB Nature. 1976; 262:326.{{cite book | title=The Liver: Biology and Pathobiology | publisher=Wiley | location=Hoboken, N.J | year=2013 | isbn=978-1-119-96422-3 | oclc=899743347 }}{{cite web | title=Hereditary Jaundice and Disorders of Bilirubin Metabolism - The Online Metabolic and Molecular Bases of Inherited Disease - McGraw-Hill Medical | website=OMMBID | date=2019-05-06 | url=https://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62639411 | access-date=2019-05-06 }}{{Dead link|date=July 2020 |bot=InternetArchiveBot |fix-attempted=yes }} and by attaching two molecules of glucuronic acid to it in a two step process.{{cite web | title=Bilirubin | website=Spencer S. Eccles Health Sciences Library Home Page | date=2019-05-06 | url=https://library.med.utah.edu/NetBiochem/hi7c.htm | archive-url=https://web.archive.org/web/20190506091832/https://library.med.utah.edu/NetBiochem/hi7c.htm | archive-date=2019-05-06 | url-status=live | access-date=2019-05-06}} The reaction is a transfer of two glucuronic acid groups including UDP glucuronic acid sequentially to the propionic acid groups of the bilirubin, primarily catalyzed by UGT1A1. In greater detail about this reaction, a glucuronosyl moiety is conjugated to one of the propionic acid side chains, located on the C8 and C12 carbons of the two central pyrrole rings of bilirubin.{{cite journal | last1=Kadakol | first1=A | last2=Ghosh | first2=SS | last3=Sappal | first3=BS | last4=Sharma | first4=G | last5=Chowdhury | first5=JR | last6=Chowdhury | first6=NR | title=Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. | journal=Human Mutation | volume=16 | issue=4 | year=2000 | issn=1059-7794 | pmid=11013440 | doi=10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z | pages=297–306| s2cid=24275067 }}

When the first step is completely done, the substrate bilirubin glucuronide (also known as mono-glucuronide) is born at this stage and is water-soluble and readily excreted in bile.[https://web.archive.org/web/20190506093216/https://library.med.utah.edu/NetBiochem/images/diglufor.gif Bilirubin must be conjugated to a water-soluble substance] Thereafter, so long as the second step of attachment of the other glucuronic acid to it succeeds (officially called "re-glucuronidated"{{cite journal | last1=Crawford | first1=JM | last2=Ransil | first2=BJ | last3=Narciso | first3=JP | last4=Gollan | first4=JL | title=Hepatic microsomal bilirubin UDP-glucuronosyltransferase. The kinetics of bilirubin mono- and diglucuronide synthesis. | journal=The Journal of Biological Chemistry | volume=267 | issue=24 | date=1992-08-25 | issn=0021-9258 | pmid=1512236 | pages=16943–50| doi=10.1016/S0021-9258(18)41876-5 | doi-access=free }}), the substrate bilirubin glucuronide will turn into bilirubin di-glucuronide (8,12-diglucuronide) and be excreted into bile canaliculi by way of C-MOAT{{noteTag | name= |1=C-MOAT is located in the canalicular membrane within the apical region of the hepatocyte.}} {{cite book | last=Cashore | first=William J. | title=Fetal and Neonatal Physiology | chapter=Neonatal Bilirubin Metabolism | publisher=Elsevier | year=2017 | isbn=978-0-323-35214-7 | doi=10.1016/b978-0-323-35214-7.00096-2 | pages=929–933 | quote=Conjugated bilirubin is excreted into canalicular bile by way of the canalicular multispecific organic anion transport (C-MOAT) system located in the canalicular membrane within the apical region of the hepatocyte. }}{{cite journal | last1=Koike | first1=K | last2=Kawabe | first2=T | last3=Tanaka | first3=T | last4=Toh | first4=S | last5=Uchiumi | first5=T | last6=Wada | first6=M | last7=Akiyama | first7=S | last8=Ono | first8=M | last9=Kuwano | first9=M | title=A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. | journal=Cancer Research | volume=57 | issue=24 | date=1997-12-15 | issn=0008-5472 | pmid=9407953 | pages=5475–9}}{{cite journal | last1=Paulusma | first1=CC | last2=van Geer | first2=MA | last3=Evers | first3=R | last4=Heijn | first4=M | last5=Ottenhoff | first5=R | last6=Borst | first6=P | last7=Oude Elferink | first7=RP | title=Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione. | journal=Biochemical Journal | volume=338 | issue=Pt 2 | date=1999-03-01 | pmid=10024515 | pmc=1220065 | pages=393–401| doi=10.1042/bj3380393 }}{{cite web | url=https://library.med.utah.edu/NetBiochem/images/normal.gif | title=Diseases Associated with Hyperbilirubinemia | date=1995-01-05 | website=library.med.utah.edu | archive-url=https://web.archive.org/web/20190506091002/https://library.med.utah.edu/NetBiochem/images/normal.gif | archive-date=2019-05-06 }} and MRP2{{cite journal | last1=Kamisako | first1=T | last2=Kobayashi | first2=Y | last3=Takeuchi | first3=K | last4=Ishihara | first4=T | last5=Higuchi | first5=K | last6=Tanaka | first6=Y | last7=Gabazza | first7=EC | last8=Adachi | first8=Y | s2cid=25491462 | title=Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance. | journal=Journal of Gastroenterology | volume=35 | issue=9 | year=2000 | issn=0944-1174 | pmid=11023036 | pages=659–64| doi=10.1007/s005350070044 }} as normal human bile along with a little amount of unconjugated bilirubin as much as only 1 to 4 percent of total pigments in normal bile.{{cite journal | last1=Erlinger | first1=Serge | last2=Arias | first2=Irwin M. | last3=Dhumeaux | first3=Daniel | title=Inherited Disorders of Bilirubin Transport and Conjugation: New Insights Into Molecular Mechanisms and Consequences | journal=Gastroenterology | volume=146 | issue=7 | year=2014 | issn=0016-5085 | pmid=24704527 | doi=10.1053/j.gastro.2014.03.047 | pages=1625–1638| doi-access=free }} That means up to 96%-99% of bilirubin in the bile are conjugated.

Normally, there is just a little conjugated bilirubin escapes into the general circulation. Nonetheless, in the setting of severe liver disease, a significantly greater number of conjugated bilirubin will leak into circulation and then dissolve into the blood{{noteTag|name=|1=Because conjugated bilirubin is water soluble and so does in blood.}} and thereby filtered by the kidney, and only a part of the leaked conjugated bilirubin will be re-absorbed in the renal tubules, the remainder will be present in the urine making it dark-colored.{{cite book | last1=Smith | first1=Margaret E. | last2=Morton | first2=Dion G. | title=The Digestive System | chapter=Liver and Biliary System | publisher=Elsevier | year=2010 | isbn=978-0-7020-3367-4 | doi=10.1016/b978-0-7020-3367-4.00006-2 | pages=[https://archive.org/details/digestivesystemb0000smit/page/85 85–105] | chapter-url=https://archive.org/details/digestivesystemb0000smit/page/85 }}