Graphical RepresentationClick to download graphical representation template
Chang Seon Ryu1, Kichul Choe1, Baeckkyoung Sung1, Seungyun Baik1, Sang Kyum Kim2 and Young Jun Kim1
1Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, Campus E 7.1, Saarbruecken, Germany
2College of Pharmacy, Chungnam National University, daehakro 99, daejeon, Republic of Korea
Point of Contact
Young Jun Kim (email point of contact)
- Young Jun Kim
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on December 03, 2019 10:04
|Inhibition of cystathionine beta-synthase||June 14, 2019 09:39|
|Increased Homocysteine level||June 14, 2019 09:45|
|Increased, Plasma HCY level||July 03, 2019 05:31|
|Induced, dysfunction of microcirculation||July 03, 2019 05:34|
|Impaired,anterior-posterior axis development||July 03, 2019 05:35|
|CBS inhibition leads to Homocysteine increases||June 14, 2019 09:53|
|Homocysteine increases leads to Plasma HCY level||July 03, 2019 05:37|
|Plasma HCY level leads to dysfunction of microcirculation||July 03, 2019 05:37|
|dysfunction of microcirculation leads to anterior-posterior axis development||July 03, 2019 05:37|
|Aminooxyacetic acid||June 14, 2019 09:57|
|S-(4-Carboxybutyl)-D,L-homocysteine; 5-(3-Amino-3-carboxypropyl)sulfanyl-pentanoic acid||June 14, 2019 09:57|
This AOP describes an adverse outcome that results from the inhibition of homocysteine (Hcy) catabolism. Hcy is a non-proteinogenic intermediary amino acid formed by the conversion of methionine to cysteine. Hcy is metabolized via two major pathways that remethylated via two remethylation pathway methionine synthase (MS) and betaine homocysteine methyltransferase (BHMT) and transsulfuration pathway enzyme, cystathionine beta-synthase (CBS). Impairment of re-methylation inhibition and/or transsulfuration lead to increment systemic concentration as known as hyperhomocysteinemia. CBS is responsible for 50% of Hcy clearance (Noga et al. 2003), together CBS is responsible for the generation of hydrogen sulfide (H2S) from cysteine (Carter and Morton, 2016). Hyperhomocysteinemia leads to increment in Hcy to the neuronal system. CBS gene was expressed in liver and kidney, skeletal, cardiac and nervous systems (Robert et al. 2003; Namekata et al. 2004). Genetic deficiency of CBS in fish is critical for axis development (Prabhudesai et al. 2018), but there is not enough evidence in early neuronal development impairment in fish by chemical inhibition. Aminooxyacetic acid is a widely used CBS inhibitor that can reduce Hcy clearance and H2S formation in the brain, has not only inhibition of CBS but also cystathione gamma-lyase. So far no selective pharmacological SBS inhibitor is currently available (Asimakopoulou et al. 2013).
Several observations indicate the involvement of hyperhomocysteinemia in neurodegeneration. Hcy levels may play a role in neuronal death via stimulation of glutamate receptors. Homocysteine is an agonist for metabotropic glutamate receptors as well as for NMDA (N-methyl-D-aspartate, as a partial antagonist) and AMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionate)/Kainate ionotropic glutamate receptors (Lazarewicz et al. 2003; Poddar and Paul 2009). Hcy further mediated subsequent Ca2+ efflux to biphasic activation of p38 mitogen-activated protein kinase (MAPK) (poddar and Paul 2013). Second possible mechanism of Hcy toxicity is free radical species production, and downregulation of antioxidant enzymes such as superoxide dismutase and peroxidase (Moat et al. 2000; Liu et al. 2013) Hcy has also been reported to modulate the expression of pro-inflammatory molecules, C-reactive protein in vascular smooth muscle cells (Pang et al. 2014). Moreover, Hcy is able to inhibit neurogenesis in the hippocampus and subventricular zone of the murine adult brain (Wang et al. 2012; Rabaneda et al. 2008). Hyperhomocysteinemia accelerates the dopaminergic cell death, probably due to the fact that hyperhomocysteinemia could cause a severe reduction in dopamine turnover in the striatum (De Lau et al. 2005).
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1657||Inhibition of cystathionine beta-synthase||CBS inhibition|
|2||KE||1661||Increased Homocysteine level||Homocysteine increases|
|3||KE||1665||Increased, Plasma HCY level||Plasma HCY level|
|4||KE||1666||Induced, dysfunction of microcirculation||dysfunction of microcirculation|
|5||AO||1667||Impaired,anterior-posterior axis development||anterior-posterior axis development|
Relationships Between Two Key Events
(Including MIEs and AOs)
|CBS inhibition leads to Homocysteine increases||adjacent||High||Low|
|Homocysteine increases leads to Plasma HCY level||adjacent||High||Moderate|
|Plasma HCY level leads to dysfunction of microcirculation||adjacent||Moderate||Low|
|dysfunction of microcirculation leads to anterior-posterior axis development||adjacent||Moderate||Low|
|S-(4-Carboxybutyl)-D,L-homocysteine; 5-(3-Amino-3-carboxypropyl)sulfanyl-pentanoic acid||High|
Life Stage Applicability
|Birth to < 1 month||High|
Overall Assessment of the AOP
This AOP is under development supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe).
Building the AOP frame
Development of KEs
Production of experimental data
Overall assessment of the AOP
Biological domain of applicability
Essentiality of all KEs
Evidence supporting all KERs
Quantitative WoE considerations
Quantitative understanding for each KER
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
This AOP is designed to detect changes of Hcy concentration in early developmental condition including fish larvae by chemical inhibition of CBS. Accumulation of neuronal damage in fish is the should be measured together in in vivo experiment for clarifing the adverse outcome. In addition, screening of selective potential chemical inhibitor of CBS will be performed in in vitro cell-based assay in different species.
Abbott MH, Folstein SE, Abbey H, Pyeritz RE. (1987) Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet. 1987 Apr; 26(4):959-69.
SJ Lee, SH Park, JF Chung, WR Choi, and HK Huh(2017) Homocysteine-induced peripheral microcirculation dysfunction in zebrafish and its attenuation by L-arginine. Oncotarget. 2017 Aug 29; 8(35): 58264–58271.
Noga AA, Stead LM, Zhao Y, Brosnan ME, Brosnan JT, Vance DE (2003) Plasma homocysteine is regulated by phospholipid methylation. J. Biol. Chem. 278, 5952–5955.
Carter RN, Morton NM. (2016) Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology J Pathol. 238(2):321-32.
Lazarewicz JW1, Ziembowicz A, Matyja E, Stafiej A, Zieminska E (2003) Homocysteine-evoked 45Ca release in the rabbit hippocampus is mediated by both NMDA and group I metabotropic glutamate receptors: in vivo microdialysis study. Neurochem Res. 28(2):259-69.
Poddar R, Paul S. (2009) Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. J Neurochem. 110(3):1095-106
Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L (2014) Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-KB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 236:73–81
De Lau LM, Koudstaal PJ, van Meurs JB, Uitterlinden AG, Hofman A, Breteler MM (2005) Methylenterahydrofolate reductase C677T genotype and PD. Annu. Neurol. 57:927–930.
Liu HH, Shih TS, Huang HR, Huang SC, Lee LH, Huang YC. (2013) Plasma homocysteine is associated with increased oxidative stress and antioxidant enzyme activity in welders. ScientificWorldJournal. 370487.
Moat SJ, Bonham JR, Cragg RA, Powers HJ.(2000) Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity. Free Radic Res. 2000 Feb;32(2):171-9.
Wang J, Bai X, Chen Y, Zhao Y, Liu X. (2012) Homocysteine induces apoptosis of rat hippocampal neurons by inhibiting 14-3-3ε expression and activating calcineurin. PLoS One. 7(11):e48247.
Rabaneda LG1, Carrasco M, López-Toledano MA, Murillo-Carretero M, Ruiz FA, Estrada C, Castro C. (2008) Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression. FASEB J. 22(11):3823-35.
Prabhudesai et al. (2018) Cystathionine β-Synthase Is Necessary for Axis Development in Vivo. Front Cell Dev Biol. 2018 Feb 16;6:14
Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol. 169(4):922-32.
J Histochem Cytochem. 2003 Mar;51(3):363-71. Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain. Robert K1, Vialard F, Thiery E, Toyama K, Sinet PM, Janel N, London J.
J Biol Chem. 2004 Dec 17;279(51):52961-9. Epub 2004 Oct 4. Abnormal lipid metabolism in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia. Namekata K1, Enokido Y, Ishii I, Nagai Y, Harada T, Kimura H.