Editing Bilirubin (section)

==History==
In ancient history, [[Hippocrates]] discussed bile pigments in two of the four [[Humorism|humours]] in the context of a relationship between yellow and black biles.<ref name=":0" /> Hippocrates visited [[Democritus]] in [[Abdera, Thrace|Abdera]] who was regarded as the expert in melancholy "black bile".<ref name=":0" />

Relevant documentation emerged in 1827 when [[Monsieur|M.]] [[Louis Jacques Thénard]] examined the [[biliary tract]] of an elephant that had died at a Paris zoo. He observed dilated bile ducts were full of yellow magma, which he isolated and found to be insoluble in water. Treating the yellow pigment with [[hydrochloric acid]] produced a strong green color. Thenard suspected the green pigment was caused by impurities derived from mucus of bile.<ref name=":0" />

[[Leopold Gmelin]] experimented with nitric acid in 1826 to establish the redox behavior in change from bilirubin to biliverdin, although the nomenclature did not exist at the time.<ref name=":0" /> The term [[biliverdin]] was coined by [[Jöns Jacob Berzelius]] in 1840, although he preferred "bilifulvin" (yellow/red) over "bilirubin" (red). The term "bilirubin" was thought to have become mainstream based on the works of Staedeler in 1864 who crystallized bilirubin from cattle gallstones.<ref name=":0" /><ref>{{cite web|last=Hian Siong Leon Maria Tjen|date=30 January 1979|title=Cholescintigraphy: The clinical application of <sup>99m</sup>Technetium-diethyl-IDA to the investigation of the liver and biliary tract. PhD thesis, Utrecht University|url=https://inis.iaea.org/collection/NCLCollectionStore/_Public/10/461/10461419.pdf|url-status=live|archive-url=https://web.archive.org/web/20211103173439/https://inis.iaea.org/collection/NCLCollectionStore/_Public/10/461/10461419.pdf |archive-date=3 November 2021 }}</ref>

[[Rudolf Virchow]] in 1847 recognized hematoidin to be identical to bilirubin.<ref>{{cite book |doi=10.1007/978-3-7091-1637-1_2 |chapter=Early Scientific Investigations |title=Bilirubin: Jekyll and Hyde Pigment of Life |volume=98 |pages=9–179 |series=Progress in the Chemistry of Organic Natural Products |year=2013 | vauthors = Lightner DA |isbn=978-3-7091-1636-4 }}</ref> It is not always distinguished from hematoidin, which one modern dictionary defines as synonymous with it<ref name="MWU">{{Citation |author=Merriam-Webster |author-link=Merriam-Webster |title=Merriam-Webster's Unabridged Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/unabridged/ |postscript=. |access-date=14 January 2018 |archive-date=25 May 2020 |archive-url=https://web.archive.org/web/20200525084504/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Funabridged%2F |url-status=dead }}</ref> but another defines as "apparently chemically identical with bilirubin but with a different site of origin, formed locally in the tissues from hemoglobin, particularly under conditions of reduced oxygen tension."<ref name="Dorlands">{{Citation |author=Elsevier |author-link=Elsevier |title=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=http://dorlands.com/ |postscript=. |access-date=14 January 2018 |archive-date=11 January 2014 |archive-url=https://web.archive.org/web/20140111192614/http://dorlands.com/ |url-status=dead }}</ref><ref name=":0">{{Cite book|last=Watson|first=Cecil J.|chapter-url=https://books.google.com/books?id=PZfDTn6BTEAC&q=irving+london+bilirubin&pg=PA9|title=International Symposium on Chemistry and Physiology of Bile Pigments|date=1977|publisher=U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health|editor-last=Berk|editor-first=Paul D.|pages=3–16|language=en|chapter=Historical Review of Bilirubin Chemistry}}</ref> The synonymous identity of bilirubin and hematoidin was confirmed in 1923 by Fischer and Steinmetz using analytical [[crystallography]].<ref name=":0" />

In the 1930s, significant advances in bilirubin isolation and synthesis were described by [[Hans Fischer]], [[:de:Hans Plieninger|Plieninger]], and others,<ref name=":0" /> and pioneering work pertaining to [[Endogeny (biology)|endogenous]] formation of bilirubin from heme was likewise conducted in the same decade.<ref name=":1">{{Cite journal|last1=Hopper|first1=Christopher P.|last2=Zambrana|first2=Paige N.|last3=Goebel|first3=Ulrich|last4=Wollborn|first4=Jakob|date=2021|title=A brief history of carbon monoxide and its therapeutic origins|url=https://linkinghub.elsevier.com/retrieve/pii/S1089860321000367|journal=Nitric Oxide|language=en|volume=111-112|pages=45–63|doi=10.1016/j.niox.2021.04.001|pmid=33838343|s2cid=233205099}}</ref> The suffix IXα is partially based on a system developed Fischer, which means the [[Bilin (biochemistry)|bilin]]'s parent compound was protoporphyrin IX cleaved at the alpha-[[Methine group|methine]] bridge (see [[Protoporphyrin IX|protoporphyrin IX nomenclature]]).<ref name=":2" />

Origins pertaining to the physiological activity of bilirubin were described by [[Ernst Stadelmann]] in 1891, who may have observed the biotransformation of infused hemoglobin into bilirubin possibly inspired by [[Ivan Tarkhanov (physiologist)|Ivan Tarkhanov]]'s 1874 works.<ref name=":0" /> [[:de:Georg Barkan|Georg Barkan]] suggested the source of endogenous bilirubin to be from hemoglobin in 1932.<ref>{{Cite journal|last1=Barkan|first1=Georg|last2=Schales|first2=Otto|date=1938|title=A Hæmoglobin from Bile Pigment|url=https://www.nature.com/articles/142836b0|journal=Nature|language=en|volume=142|issue=3601|pages=836–837|doi=10.1038/142836b0|bibcode=1938Natur.142..836B|s2cid=4073510|issn=1476-4687}}</ref> Plieninger and Fischer demonstrated an enzymatic oxidative loss of the alpha-[[Methine group|methine]] bridge of heme resulting in a bis-lactam structure in 1942.<ref name=":0" /> It is widely accepted that [[Irving London]] was the first to demonstrate endogenous formation of bilirubin from hemoglobin in 1950,<ref>{{cite web|title=Bilirubin|url=https://www.acs.org/content/acs/en/molecule-of-the-week/archive/b/bilirubin.html|access-date=2021-05-28|website=American Chemical Society|language=en}}</ref> and Sjostrand demonstrated hemoglobin catabolism produces [[carbon monoxide]] between 1949 and 1952.<ref name=":1" /> 14C labeled protoporphyrin biotransformation to bilirubin evidence emerged in 1966 by [[Cecil Watson]].<ref name=":0" /> [[Rudi Schmid]] and Tenhunen discovered [[heme oxygenase]], the enzyme responsible, in 1968.<ref name=":1" />  Earlier in 1963, Nakajima described a soluble "heme alpha-methnyl oxygeanse" which what later determined to be a non-enzymatic pathway, such as formation of a [[1,2-Dioxetane]] intermediate at the methine bridge resulting in carbon monoxide release and biliverdin formation.<ref name=":2">{{Cite book|last1=Berk|first1=Paul D.|url=https://books.google.com/books?id=PZfDTn6BTEAC&q=monoxide&pg=PA9|title=International Symposium on Chemistry and Physiology of Bile Pigments|last2=Berlin|first2=Nathaniel I.|date=1977|publisher=U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health|pages=27, 50|language=en}}</ref>