Ophthalmic acid

{{Chembox | Verifiedfields = changed | Watchedfields = changed | Reference = <ref>{{Cite web |url=http://www.hmdb.ca/scripts/show_card.cgi?METABOCARD=HMDB05765.txt |title=Ophthalmic acid |access-date=2007-07-03 |archive-date=2007-10-06 |archive-url=https://web.archive.org/web/20071006120440/http://www.hmdb.ca/scripts/show_card.cgi?METABOCARD=HMDB05765.txt }}</ref> | verifiedrevid = 458635907 | ImageFile = Ophthalmic acid.png | ImageFile_Ref = {{chemboximage|correct|??}} | ImageName = Stereo, skeletal formula of ophthalmic acid | IUPACName = (''N''-(L-γ-Glutamyl)-(2''S'')-2-aminobutyryl)glycine |Section1={{Chembox Identifiers | CASNo = 495-27-2 | CASNo_Ref = {{cascite|correct|CAS}} | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 3A60475Q1Q | PubChem = 7018721 | ChemSpiderID = 5381695 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 84058 | MeSHName = ophthalmic+acid | SMILES = CC[C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)NCC(O)=O | SMILES2 = | StdInChI = 1S/C11H19N3O6/c1-2-7(10(18)13-5-9(16)17)14-8(15)4-3-6(12)11(19)20/h6-7H,2-5,12H2,1H3,(H,13,18)(H,14,15)(H,16,17)(H,19,20)/t6-,7-/m0/s1 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = JCMUOFQHZLPHQP-BQBZGAKWSA-N | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} }} |Section2={{Chembox Properties | C=11 | N=3 | H=19 | O=6 | Appearance = White crystals }} |Section3={{Chembox Related | OtherFunction_label = alkanoic acids | OtherFunction = {{unbulleted list|''N''-Acetylaspartylglutamic acid|Glycylglycine|α-Aminobutyric acid}} | OtherCompounds = }} }}

'''Ophthalmic acid (OPH)''', also known as ophthalmate (chemically L-γ-glutamyl-L-α-aminobutyrylglycine), is a tripeptide analog of glutathione. However, instead of the cysteine essential for many of glutathione's diverse functions, it contains L-2-aminobutyrate, a non-proteinogenic amino acid lacking the nucleophilic thiol group. Because of this, it has been widely, and incorrectly, considered an accidental byproduct of glutathione synthesis.

In 2024, an article published by the federation of European biochemistry societies compiled evidence to put forward the major hypothesis that OPH serves as a glutathione regulating tripeptide, affecting both cellular and organelle influx and efflux of GSH, as well as modulating GSH-dependent reactions and signaling.<ref name=":14">{{Cite journal |last=Schomakers |first=Bauke V. |last2=Jillings |first2=Sonia L. |last3=van Weeghel |first3=Michel |last4=Vaz |first4=Frédéric M. |last5=Salomons |first5=Gajja S. |last6=Janssens |first6=Georges E. |last7=Houtkooper |first7=Riekelt H. |date=2024-01-20 |title=Ophthalmic acid is a glutathione regulating tripeptide |url=https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.17061 |journal=The FEBS Journal |language=en |doi=10.1111/febs.17061 |issn=1742-464X|doi-access=free }}</ref>

==Biosynthesis== OPH is created using the precursor 2-aminobutyric acid through consecutive reactions of the same enzymes that create GSH, namely Glutamate–cysteine ligase and glutathione synthetase.

Major regulators of OPH biosynthesis are local (relative) concentrations of cysteine and 2-aminobutyric acid, as well as their γ-glutamyl intermediate products.<ref name=":14" />

== Discovery and occurrence == OPH was first discovered and isolated from calf lens<ref>Waley SG; Biochem. J. 64, 715 (1956)</ref> in 1956, and has since been found to be a ubiquitous metabolite. It is produced by:

* Various bacteria<ref>{{Cite journal |last1=Narainsamy |first1=Kinsley |last2=Farci |first2=Sandrine |last3=Braun |first3=Emilie |last4=Junot |first4=Christophe |last5=Cassier-Chauvat |first5=Corinne |last6=Chauvat |first6=Franck |date=2016-02-09 |title=Oxidative-stress detoxification and signalling in cyanobacteria: the crucial glutathione synthesis pathway supports the production of ergothioneine and ophthalmate |journal=Molecular Microbiology |volume=100 |issue=1 |pages=15–24 |doi=10.1111/mmi.13296 |issn=0950-382X |doi-access=free |pmid=26713511 }}</ref><ref>{{Cite journal |last1=Ito |first1=Tomokazu |last2=Yamauchi |first2=Ayako |last3=Hemmi |first3=Hisashi |last4=Yoshimura |first4=Tohru |date=December 2016 |title=Ophthalmic acid accumulation in an Escherichia coli mutant lacking the conserved pyridoxal 5′-phosphate-binding protein YggS |journal=Journal of Bioscience and Bioengineering |volume=122 |issue=6 |pages=689–693 |doi=10.1016/j.jbiosc.2016.06.010 |pmid=27426274 |issn=1389-1723}}</ref> * Fungi<ref>{{Cite journal |last1=Fountain |first1=Jake C. |last2=Yang |first2=Liming |last3=Pandey |first3=Manish K. |last4=Bajaj |first4=Prasad |last5=Alexander |first5=Danny |last6=Chen |first6=Sixue |last7=Kemerait |first7=Robert C. |last8=Varshney |first8=Rajeev K. |last9=Guo |first9=Baozhu |title=Carbohydrate, glutathione, and polyamine metabolism are central to Aspergillus flavus oxidative stress responses over time |journal=BMC Microbiology |date=2019 |volume=19 |issue=1 |article-number=209 |doi=10.1186/s12866-019-1580-x |doi-access=free |pmid=31488075 |pmc=6727485 |biorxiv=10.1101/511170}}</ref> * Phylogenetically distant plants<ref name=":0">{{Cite journal |last1=Servillo |first1=Luigi |last2=Castaldo |first2=Domenico |last3=Giovane |first3=Alfonso |last4=Casale |first4=Rosario |last5=D'Onofrio |first5=Nunzia |last6=Cautela |first6=Domenico |last7=Balestrieri |first7=Maria Luisa |date=April 2018 |title=Ophthalmic acid is a marker of oxidative stress in plants as in animals |journal=Biochimica et Biophysica Acta (BBA) - General Subjects |volume=1862 |issue=4 |pages=991–998 |doi=10.1016/j.bbagen.2018.01.015 |pmid=29413907 |issn=0304-4165}}</ref><ref name=":1">{{Cite journal |last1=Pinsorn |first1=Pinnapat |last2=Oikawa |first2=Akira |last3=Watanabe |first3=Mutsumi |last4=Sasaki |first4=Ryosuke |last5=Ngamchuachit |first5=Panita |last6=Hoefgen |first6=Rainer |last7=Saito |first7=Kazuki |last8=Sirikantaramas |first8=Supaart |date=December 2018 |title=Metabolic variation in the pulps of two durian cultivars: Unraveling the metabolites that contribute to the flavor |journal=Food Chemistry |volume=268 |pages=118–125 |doi=10.1016/j.foodchem.2018.06.066 |pmid=30064738 |issn=0308-8146}}</ref><ref name=":2">{{Cite journal |last1=Baxter |first1=Bridget |last2=Oppel |first2=Renee |last3=Ryan |first3=Elizabeth |date=2018-12-22 |title=Navy Beans Impact the Stool Metabolome and Metabolic Pathways for Colon Health in Cancer Survivors |journal=Nutrients |volume=11 |issue=1 |page=28 |doi=10.3390/nu11010028 |issn=2072-6643 |pmc=6356708 |doi-access=free |pmid=30583518 }}</ref> * Nematodes<ref>{{Cite journal |last1=Schomakers |first1=Bauke V. |last2=Hermans |first2=Jill |last3=Jaspers |first3=Yorrick R.J. |last4=Salomons |first4=Gajja |last5=Vaz |first5=Frédéric M. |last6=van Weeghel |first6=Michel |last7=Houtkooper |first7=Riekelt H. |date=June 2022 |title=Polar metabolomics in human muscle biopsies using a liquid-liquid extraction and full-scan LC-MS |journal=STAR Protocols |volume=3 |issue=2 |article-number=101302 |doi=10.1016/j.xpro.2022.101302 |issn=2666-1667 |pmc=9035783 |doi-access=free |pmid=35479116 }}</ref> like C. elegans * Insects<ref name=":10">{{Cite journal |last1=Ryabova |first1=Alina |last2=Cornette |first2=Richard |last3=Cherkasov |first3=Alexander |last4=Watanabe |first4=Masahiko |last5=Okuda |first5=Takashi |last6=Shagimardanova |first6=Elena |last7=Kikawada |first7=Takahiro |last8=Gusev |first8=Oleg |date=2020-07-28 |title=Combined metabolome and transcriptome analysis reveals key components of complete desiccation tolerance in an anhydrobiotic insect |journal=Proceedings of the National Academy of Sciences |volume=117 |issue=32 |pages=19209–19220 |doi=10.1073/pnas.2003650117 |issn=0027-8424 |pmc=7431039 |doi-access=free |pmid=32723826 |bibcode=2020PNAS..11719209R }}</ref> * Fish<ref>{{Cite journal |last1=Remø |first1=Sofie Charlotte |last2=Hevrøy |first2=Ernst Morten |last3=Breck |first3=Olav |last4=Olsvik |first4=Pål Asgeir |last5=Waagbø |first5=Rune |date=2017-04-18 |title=Lens metabolomic profiling as a tool to understand cataractogenesis in Atlantic salmon and rainbow trout reared at optimum and high temperature |journal=PLOS ONE |volume=12 |issue=4 |article-number=e0175491 |doi=10.1371/journal.pone.0175491 |issn=1932-6203 |pmc=5395160 |doi-access=free |pmid=28419112 |bibcode=2017PLoSO..1275491R }}</ref> * Birds<ref name=":11">{{Cite journal |last1=Abasht |first1=Behnam |last2=Mutryn |first2=Marie F. |last3=Michalek |first3=Ryan D. |last4=Lee |first4=William R. |date=2016-04-20 |title=Oxidative Stress and Metabolic Perturbations in Wooden Breast Disorder in Chickens |journal=PLOS ONE |volume=11 |issue=4 |article-number=e0153750 |doi=10.1371/journal.pone.0153750 |issn=1932-6203 |pmc=4838225 |doi-access=free |pmid=27097013 |bibcode=2016PLoSO..1153750A }}</ref> * Various rodents<ref name=":3">{{Cite journal |last1=Orlowski |first1=M |last2=Wilk |first2=S |date=1978-02-15 |title=Synthesis of ophthalmic acid in liver and kidney ''in vivo'' |journal=Biochemical Journal |volume=170 |issue=2 |pages=415–419 |doi=10.1042/bj1700415 |issn=0306-3283 |pmc=1183909 |pmid=637852}}</ref><ref name=":4">{{Cite journal |last1=Andres Ibarra |first1=Rafael |last2=Abbas |first2=R. |last3=Kombu |first3=R. S. |last4=Zhang |first4=Guo-Fang |last5=Jacobs |first5=G. |last6=Lee |first6=Z. |last7=Brunengraber |first7=H. |last8=Sanabria |first8=J. R. |date=2011-09-18 |title=Disturbances in the Glutathione/Ophthalmate Redox Buffer System in the Woodchuck Model of Hepatitis Virus-Induced Hepatocellular Carcinoma |journal=HPB Surgery |volume=2011 |pages=1–9 |doi=10.1155/2011/789323 |issn=0894-8569 |pmc=3175733 |doi-access=free |pmid=21941408 }}</ref><ref name=":5">{{Cite journal |last1=Tsuboi |first1=Seiji |last2=Hirota |first2=Kazuhiro |last3=Ogata |first3=Kazumi |last4=Ohmori |first4=Shinji |date=February 1984 |title=Ophthalmic and norophthalmic acid in lens, liver, and brain of higher animals |journal=Analytical Biochemistry |volume=136 |issue=2 |pages=520–524 |doi=10.1016/0003-2697(84)90255-0 |pmid=6721150 |issn=0003-2697}}</ref><ref name=":6">{{Cite journal |last1=Maekawa |first1=Keiko |last2=Hirayama |first2=Akiyoshi |last3=Iwata |first3=Yuko |last4=Tajima |first4=Yoko |last5=Nishimaki-Mogami |first5=Tomoko |last6=Sugawara |first6=Shoko |last7=Ueno |first7=Noriko |last8=Abe |first8=Hiroshi |last9=Ishikawa |first9=Masaki |last10=Murayama |first10=Mayumi |last11=Matsuzawa |first11=Yumiko |last12=Nakanishi |first12=Hiroki |last13=Ikeda |first13=Kazutaka |last14=Arita |first14=Makoto |last15=Taguchi |first15=Ryo |date=June 2013 |title=Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy |journal=Journal of Molecular and Cellular Cardiology |volume=59 |pages=76–85 |doi=10.1016/j.yjmcc.2013.02.008 |pmid=23454301 |issn=0022-2828}}</ref> * Lagomorphs<ref name=":5" /> like rabbits * Mammals<ref name="Sethna 923–928">{{Cite journal |last1=Sethna |first1=Shirley S. |last2=Gander |first2=John E. |last3=Rathbun |first3=William B. |date=January 1984 |title=Glutathione synthetase of bovine lens: Anomalies of the enzyme-catalyzed formation of ophthalmic acid |journal=Current Eye Research |volume=3 |issue=7 |pages=923–928 |doi=10.3109/02713688409167209 |pmid=6547896 |issn=0271-3683}}</ref><ref>{{Cite journal |last=Waley |first=S. G. |date=1958-01-01 |title=Acidic peptides of the lens. 3. The structure of ophthalmic acid |journal=Biochemical Journal |volume=68 |issue=1 |pages=189–192 |doi=10.1042/bj0680189 |issn=0306-3283 |pmc=1200251 |pmid=13522597}}</ref><ref name=":5" /><ref>{{Cite journal |last1=Schønheyder |first1=F. |last2=Ehlers |first2=N. |last3=Hust |first3=B. |date=September 1975 |title=Remarks on the Aqueous Humor/Plasma Ratios for Amino Acids and Related Compounds in Patients With Various Chronic Ocular Disorders |journal=Acta Ophthalmologica |volume=53 |issue=4 |pages=627–634 |doi=10.1111/j.1755-3768.1975.tb01781.x |pmid=1242283 |issn=1755-375X}}</ref> (including humans<ref name=":2" /><ref>{{Cite journal |last1=Kombu |first1=Rajan S. |last2=Zhang |first2=Guo-Fang |last3=Abbas |first3=Rime |last4=Mieyal |first4=John J. |last5=Anderson |first5=Vernon E. |last6=Kelleher |first6=Joanne K. |last7=Sanabria |first7=Juan R. |last8=Brunengraber |first8=Henri |date=July 2009 |title=Dynamics of glutathione and ophthalmate traced with2H-enriched body water in rats and humans |journal=American Journal of Physiology. Endocrinology and Metabolism |volume=297 |issue=1 |pages=E260–E269 |doi=10.1152/ajpendo.00080.2009 |issn=0193-1849 |pmc=2711657 |pmid=19401458}}</ref><ref name=":7">{{Cite journal |last1=Janssens |first1=Georges E. |last2=Grevendonk |first2=Lotte |last3=Perez |first3=Ruben Zapata |last4=Schomakers |first4=Bauke V. |last5=de Vogel-van den Bosch |first5=Johan |last6=Geurts |first6=Jan M. W. |last7=van Weeghel |first7=Michel |last8=Schrauwen |first8=Patrick |last9=Houtkooper |first9=Riekelt H. |last10=Hoeks |first10=Joris |date=2022-02-17 |title=Healthy aging and muscle function are positively associated with NAD+ abundance in humans |journal=Nature Aging |volume=2 |issue=3 |pages=254–263 |doi=10.1038/s43587-022-00174-3 |pmid=37118369 |issn=2662-8465}}</ref><ref>{{Cite web |last1=Garcia-Tsao |first1=Guadalupe |last2=Fortune |first2=Brett |date=2013-01-30 |title=Faculty of 1000 evaluation for Systematic review of ophthalmate as a novel biomarker of hepatic glutathione depletion. |doi=10.3410/f.717969185.793470080 |doi-access=free}}</ref><ref>{{Cite journal |last1=Kim Mc Van |first1=M. |last2=Dello |first2=S. A. |last3=De Jong |first3=M. C. |last4=Van Eijk |first4=H. M. |last5=De Kok |first5=T. M. |last6=Briedé |first6=J. J. |last7=Schaap |first7=F. G. |last8=Damink |first8=S. W. |last9=Dejong |first9=C. H. |date=2017 |title=Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans |journal=Journal of Clinical and Translational Research |volume=3 |issue=Suppl 2 |pages=366–374 |doi=10.18053/jctres.03.2017s2.006 |issn=2424-810X |pmc=6412618 |doi-access=free |pmid=30873484 }}</ref><ref name=":8">{{Cite journal |last1=Kondoh |first1=Hiroshi |last2=Kameda |first2=Masahiro |last3=Yanagida |first3=Mitsuhiro |date=2020-12-26 |title=Whole Blood Metabolomics in Aging Research |journal=International Journal of Molecular Sciences |volume=22 |issue=1 |page=175 |doi=10.3390/ijms22010175 |issn=1422-0067 |pmc=7796096 |doi-access=free |pmid=33375345 }}</ref><ref name=":12">{{Cite journal |last1=Priolo |first1=Carmen |last2=Khabibullin |first2=Damir |last3=Reznik |first3=Ed |last4=Filippakis |first4=Harilaos |last5=Ogórek |first5=Barbara |last6=Kavanagh |first6=Taylor R. |last7=Nijmeh |first7=Julie |last8=Herbert |first8=Zachary T. |last9=Asara |first9=John M. |last10=Kwiatkowski |first10=David J. |last11=Wu |first11=Chin-Lee |last12=Henske |first12=Elizabeth P. |date=2018-06-11 |title=Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma |journal=Proceedings of the National Academy of Sciences |volume=115 |issue=27 |pages=E6274–E6282 |doi=10.1073/pnas.1710849115 |issn=0027-8424 |pmc=6142242 |doi-access=free |pmid=29891694 |bibcode=2018PNAS..115E6274P }}</ref><ref name=":9">{{Cite journal |last1=Fong |first1=Miranda Y. |last2=McDunn |first2=Jonathan |last3=Kakar |first3=Sham S. |date=2011-05-19 |title=Identification of Metabolites in the Normal Ovary and Their Transformation in Primary and Metastatic Ovarian Cancer |journal=PLOS ONE |volume=6 |issue=5 |article-number=e19963 |doi=10.1371/journal.pone.0019963 |issn=1932-6203 |pmc=3098284 |doi-access=free |pmid=21625518 |bibcode=2011PLoSO...619963F }}</ref><ref>{{Cite web |last1=Admin |first1=Ada |last2=Pipino |first2=Caterina |last3=Shah |first3=Hetal |last4=Prudente |first4=Sabrina |last5=Pietro |first5=Natalia Di |last6=Zeng |first6=Lixia |last7=Park |first7=Kyoungmin |last8=Trischitta |first8=Vincenzo |last9=Pennathur |first9=Subramanian |date=2020-07-10 |title=Association of the 1q25 diabetes-specific coronary heart disease locus with alterations of the γ-glutamyl cycle and increased methylglyoxal levels in endothelial cells |doi=10.2337/figshare.12616442}}</ref><ref>{{Cite journal |last1=Kameda |first1=Masahiro |last2=Teruya |first2=Takayuki |last3=Yanagida |first3=Mitsuhiro |last4=Kondoh |first4=Hiroshi |date=2020-04-15 |title=Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility |journal=Proceedings of the National Academy of Sciences |volume=117 |issue=17 |pages=9483–9489 |doi=10.1073/pnas.1920795117 |issn=0027-8424 |pmc=7196897 |doi-access=free |pmid=32295884 |bibcode=2020PNAS..117.9483K }}</ref><ref>{{Cite journal |last1=Chaleckis |first1=Romanas |last2=Murakami |first2=Itsuo |last3=Takada |first3=Junko |last4=Kondoh |first4=Hiroshi |last5=Yanagida |first5=Mitsuhiro |date=2016-03-28 |title=Individual variability in human blood metabolites identifies age-related differences |journal=Proceedings of the National Academy of Sciences |volume=113 |issue=16 |pages=4252–4259 |doi=10.1073/pnas.1603023113 |issn=0027-8424 |pmc=4843419 |doi-access=free |pmid=27036001 |bibcode=2016PNAS..113.4252C }}</ref><ref>{{Cite journal |last1=Masood |first1=Afshan |last2=Jacob |first2=Minnie |last3=Gu |first3=Xinyun |last4=Abdel Jabar |first4=Mai |last5=Benabdelkamel |first5=Hicham |last6=Nizami |first6=Imran |last7=Li |first7=Liang |last8=Dasouki |first8=Majed |last9=Abdel Rahman |first9=Anas M. |date=January 2021 |title=Distinctive metabolic profiles between Cystic Fibrosis mutational subclasses and lung function |journal=Metabolomics |volume=17 |issue=1 |article-number=4 |doi=10.1007/s11306-020-01760-5 |pmid=33394183 |issn=1573-3882}}</ref>)

Distribution within (higher) organisms also appears to be ubiquitous as it has been found in the:

* Brain<ref name=":5" /> * Eye<ref name=":5" /> * Liver<ref name=":5" /><ref name=":3" /> * Kidney<ref name=":3" /> * Heart<ref name=":6" /> * Gonads<ref>{{Cite journal |last1=Feuer |first1=Sky K. |last2=Donjacour |first2=Annemarie |last3=Simbulan |first3=Rhodel K. |last4=Lin |first4=Wingka |last5=Liu |first5=Xiaowei |last6=Maltepe |first6=Emin |last7=Rinaudo |first7=Paolo F. |date=2014-11-01 |title=Sexually Dimorphic Effect of In Vitro Fertilization (IVF) on Adult Mouse Fat and Liver Metabolomes |journal=Endocrinology |volume=155 |issue=11 |pages=4554–4567 |doi=10.1210/en.2014-1465 |issn=0013-7227 |pmc=4197990 |doi-access=free |pmid=25211591 }}</ref> * Ovaries<ref name=":9" /> * muscles<ref name=":7" /> * Adipose tissue<ref>{{Cite journal |last1=Offord |first1=R E |last2=Philippe |first2=J |last3=Davis |first3=J G |last4=Halban |first4=P A |last5=Berger |first5=M |date=1979-07-15 |title=Inhibition of degradation of insulin by ophthalamic acid and by a bovine pancreatic proteinase inhibitor |journal=Biochemical Journal |volume=182 |issue=1 |pages=249–251 |doi=10.1042/bj1820249 |issn=0264-6021 |pmc=1161257 |pmid=315228}}</ref> * Blood<ref name=":8" /> * Plasma<ref name=":13">{{Cite journal |last1=Soga |first1=Tomoyoshi |last2=Baran |first2=Richard |last3=Suematsu |first3=Makoto |last4=Ueno |first4=Yuki |last5=Ikeda |first5=Satsuki |last6=Sakurakawa |first6=Tadayuki |last7=Kakazu |first7=Yuji |last8=Ishikawa |first8=Takamasa |last9=Robert |first9=Martin |last10=Nishioka |first10=Takaaki |last11=Tomita |first11=Masaru |date=June 2006 |title=Differential Metabolomics Reveals Ophthalmic Acid as an Oxidative Stress Biomarker Indicating Hepatic Glutathione Consumption |journal=Journal of Biological Chemistry |volume=281 |issue=24 |pages=16768–16776 |doi=10.1074/jbc.m601876200 |issn=0021-9258 |doi-access=free |pmid=16608839 |bibcode=2006JBiCh.28116768S }}</ref> * Erythrocytes<ref name=":4" /> * Human feces<ref name=":2" />

In plants, it is found in:

* Seed flour<ref name=":0" /> * Leaves<ref name=":0" /> * Fruit pulp<ref name=":1" /> * Beans<ref name=":2" />

== Ophthalmic acid is not a biomarker of oxidative stress == OPH has mostly appeared in metabolomics studies correlating changes in its abundance with oxidative stress, following a study from 2006 on acetaminophen overdose in mice.<ref name=":13" /> However, this practice should generally be avoided, as there are major issues:

# Though some studies indeed find this correlation,<ref name=":0" /><ref>{{Cite journal |last1=Carretero |first1=Aitor |last2=León |first2=Zacarías |last3=García-Cañaveras |first3=Juan Carlos |last4=Zaragoza |first4=Ángela |last5=Gómez-Lechón |first5=María José |last6=Donato |first6=María Teresa |last7=Lahoz |first7=Agustín |date=2014-06-27 |title=In vitro/in vivo screening of oxidative homeostasis and damage to DNA, protein, and lipids using UPLC/MS-MS |journal=Analytical and Bioanalytical Chemistry |volume=406 |issue=22 |pages=5465–5476 |doi=10.1007/s00216-014-7983-5 |issn=1618-2642}}</ref> the consistent correlation between ophthalmic acid increases and glutathione depletion does not exist. Compared to a healthy baseline, both can go up,<ref name=":11" /><ref name=":12" /> both can go down,<ref>{{Cite journal |last1=Brunelli |first1=Laura |last2=Caiola |first2=Elisa |last3=Marabese |first3=Mirko |last4=Broggini |first4=Massimo |last5=Pastorelli |first5=Roberta |date=2014-05-12 |title=Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells |journal=Oncotarget |volume=5 |issue=13 |pages=4722–4731 |doi=10.18632/oncotarget.1958 |issn=1949-2553|doi-access=free |pmc=4148094 }}</ref><ref>{{Cite journal |last1=Mehta |first1=Hemal H. |last2=Xiao |first2=Jialin |last3=Ramirez |first3=Ricardo |last4=Miller |first4=Brendan |last5=Kim |first5=Su-Jeong |last6=Cohen |first6=Pinchas |last7=Yen |first7=Kelvin |date=June 2019 |title=Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment |journal=Metabolomics |volume=15 |issue=6 |doi=10.1007/s11306-019-1549-7 |issn=1573-3882|doi-access=free |pmc=6554247 }}</ref> or ophthalmic acid can go up with no changes in glutathione.<ref name=":9" /><ref>{{Cite journal |last1=Lee |first1=Jaeyong |last2=Kang |first2=Eun Sil |last3=Kobayashi |first3=Sho |last4=Homma |first4=Takujiro |last5=Sato |first5=Hideyo |last6=Seo |first6=Han Geuk |last7=Fujii |first7=Junichi |date=December 2017 |title=The viability of primary hepatocytes is maintained under a low cysteine-glutathione redox state with a marked elevation in ophthalmic acid production |journal=Experimental Cell Research |volume=361 |issue=1 |pages=178–191 |doi=10.1016/j.yexcr.2017.10.017 |issn=0014-4827}}</ref><ref name=":10" /> A study on circadian rhythm tracking both glutathione and ophthalmic acid levels determined that ophthalmic acid levels were rhythmic, while glutathione levels were not.<ref>{{Cite journal |last1=Goede |first1=Paul |last2=Wüst |first2=Rob C. I. |last3=Schomakers |first3=Bauke V. |last4=Denis |first4=Simone |last5=Vaz |first5=Frédéric M. |last6=Pras‐Raves |first6=Mia L. |last7=Weeghel |first7=Michel |last8=Yi |first8=Chun‐Xia |last9=Kalsbeek |first9=Andries |last10=Houtkooper |first10=Riekelt H. |date=2022-01-15 |title=Time‐restricted feeding during the inactive phase abolishes the daily rhythm in mitochondrial respiration in rat skeletal muscle |journal=The FASEB Journal |volume=36 |issue=2 |doi=10.1096/fj.202100707r |issn=0892-6638|doi-access=free |hdl=20.500.11755/74eab261-4c7d-4293-b7fb-8389b96134d7 |hdl-access=free }}</ref> Ophthalmic acid trends also differ wildly between different tissues in the same animal at the same timepoint,<ref name="ReferenceA">{{Cite journal |date=2017 |title=Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans |journal=Journal of Clinical and Translational Research |doi=10.18053/jctres.03.2017s2.006 |issn=2424-810X|doi-access=free |pmc=6412618 }}</ref><ref>{{Cite journal |last1=Ghosh |first1=Sujoy |last2=Forney |first2=Laura A. |last3=Wanders |first3=Desiree |last4=Stone |first4=Kirsten P. |last5=Gettys |first5=Thomas W. |date=2017-05-16 |title=An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice |journal=PLOS ONE |volume=12 |issue=5 |article-number=e0177513 |doi=10.1371/journal.pone.0177513 |issn=1932-6203|doi-access=free |pmc=5433721 }}</ref> again dispelling the notion of a broader and consistent correlation. # The meaning of "biomarker" is much more narrow in this context than many studies assume. Importantly, the Soga et al. study sees a correlation between depleting hepatic glutathione levels, and rising ophthalmic acid levels in plasma, in mice. It solves the practical problem of not being able to directly measure an established glutathione depletion in liver by measuring ophthalmic acid in plasma. However, subsequent studies often measure both glutathione and ophthalmic acid, and when glutathione shows no aberration, ophthalmic acid is used as a "marker" to still claim oxidative stress. There cannot be an appeal to a correlation when the data itself disproves that very correlation. # Ophthalmic acid can be found in high concentrations in healthy tissues. For instance in the eye.<ref name="Sethna 923–928" /> It is not solely found in stressed or diseased states. # The original goal of using ophthalmic acid plasma levels to assess liver damage after acetaminophen overdose has not proven effective in several follow-up studies.<ref>{{Cite journal |last1=Kaur |first1=Gurnit |last2=Leslie |first2=Elaine M. |last3=Tillman |first3=Holly |last4=Lee |first4=William M. |last5=Swanlund |first5=Diane P. |last6=Karvellas |first6=Constantine J. |date=2015-09-25 |title=Detection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors |journal=PLOS ONE |volume=10 |issue=9 |article-number=e0139299 |doi=10.1371/journal.pone.0139299 |issn=1932-6203|doi-access=free |pmc=4583290 }}</ref><ref name="ReferenceA"/>

==References== {{reflist}}

Category:Tripeptides