# Monocrotaline
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> Markdown URL: https://mediated.wiki/source/Monocrotaline.md
> Source: https://en.wikipedia.org/wiki/Monocrotaline
> Source revision: 1332928050
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| ImageName = Skeleton formula of a carbon ring, containing oxygen, hydrogen and nitrogen atoms. It is supposed to be monocrotaline
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| ImageCaption = Chemical structure of monocrotaline
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| OtherNames = {{Unbulleted list
| Crotaline
| (-)-Monocrotaline
| Retronecine cyclic 2,3-dihydroxy-2,3,4-trimethylglutarate
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| IUPACName = (1''R'',4''R'',5''R'',6''R'',16''R'')-5,6-dihydroxy-4,5,6-trimethyl-2,8-dioxa-13-azatricyclo[8.5.1.013,16]hexadec-10-ene-3,7-dione
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| CASNo = 315-22-0
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| UNII = 73077K8HYV
| ChEBI = 6980
| ChEMBL = 521035
| ChemSpiderID = 9044
| EINECS = 628-506-2
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| KEGG = C10350
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| PubChem = 9415
| StdInChI=1S/C16H23NO6/c1-9-13(18)23-11-5-7-17-6-4-10(12(11)17)8-22-14(19)16(3,21)15(9,2)20/h4,9,11-12,20-21H,5-8H2,1-3H3/t9-,11+,12+,15+,16-/m0/s1
| StdInChIKey = QVCMHGGNRFRMAD-XFGHUUIASA-N
| SMILES = C[C@H]1C(=O)O[C@@H]2CCN3[C@@H]2C(=CC3)COC(=O)[C@]([C@]1(C)O)(C)O
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| LD50 = 66 mg/kg (rat, oral) / 259 mg/kg (mouse) intravenous)
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'''Monocrotaline''' ('''MCT''') is a [pyrrolizidine alkaloid](/source/pyrrolizidine_alkaloid) that is present in plants of the ''[Crotalaria](/source/Crotalaria)'' genus. These species can synthesise MCT out of [amino acid](/source/amino_acid)s and can cause [liver](/source/liver), [lung](/source/lung) and [kidney](/source/kidney) damage in various organisms. Initial stress factors are released intracellular upon binding of MCT to BMPR2 receptors and elevated MAPK phosphorylation levels are induced, which can cause [cancer](/source/cancer) in ''Homo sapiens''. MCT can be detoxified in rats via [oxidation](/source/Redox), followed by [glutathione-conjugation](/source/Glutathione_conjugation) and [hydrolysis](/source/hydrolysis).
== Origin ==
287x287px|Picture of the ''Crotalaria spectabilis.''|alt=Picture of the Crotalaria spectabilis.|thumb|left
MCT occurs in the seeds of certain species of the genus ''[Crotalaria](/source/Crotalaria)'', for example, ''[Crotalaria spectabilis](/source/Crotalaria_spectabilis)'' and ''[Crotalaria mucronata](/source/Crotalaria_mucronata)''.[{{Cite journal|last1=Gomez-Arroyo|first1=Jose G.|last2=Farkas|first2=Laszlo|last3=Alhussaini|first3=Aysar A.|last4=Farkas|first4=Daniela|last5=Kraskauskas|first5=Donatas|last6=Voelkel|first6=Norbert F.|last7=Bogaard|first7=Harm J.|date=2012-02-15|title=The monocrotaline model of pulmonary hypertension in perspective|url=http://dx.doi.org/10.1152/ajplung.00212.2011|journal=American Journal of Physiology. Lung Cellular and Molecular Physiology|volume=302|issue=4|pages=L363–L369|doi=10.1152/ajplung.00212.2011|pmid=21964406|s2cid=14342793 |issn=1040-0605|url-access=subscription}}] MCT is a chemical with pesticide properties and therefore serves as a defence mechanism to fend off predators. However, it can also lead to the poisoning of mammals and birds.[{{Cite journal|last1=Williams|first1=M. Coburn|last2=Molyneux|first2=Russell J.|date=1987|title=Occurrence, Concentration, and Toxicity of Pyrrolizidine Alkaloids in Crotalaria Seeds|url=https://www.cambridge.org/core/journals/weed-science/article/abs/occurrence-concentration-and-toxicity-of-pyrrolizidine-alkaloids-in-crotalaria-seeds/EF67697B2DC5C692EA26E97E46FBE47B|journal=Weed Science|language=en|volume=35|issue=4|pages=476–481|doi=10.1017/S0043174500060410|bibcode=1987WeedS..35..476W |s2cid=91434059 |issn=0043-1745|url-access=subscription}}]
The butterfly ''[Utetheisa ornatrix](/source/Utetheisa_ornatrix)'' also benefits from MCT by using it as protection. The larvae of the butterfly feed almost exclusively on ''Crotalaria'' seeds, where MCT is accumulated in their bodies. In this way, they are protected from predators such as spiders for the rest of their lives (even after pupation as butterflies).[{{Cite book|last=Everist|first=S. L.|url=https://www.biblio.com/book/poisonous-plants-australia-everist-sl/d/714909030|title=Poisonous plants of Australia|date=1974|publisher=Angus & Robertson|isbn=978-0-207-12773-1|edition=1|location=Sydney}}]
== Toxicity ==
MCT is an acute toxic substance. The toxicity of MCT is dose-dependent, and it can harm both organs and genetic material ([genotoxicity](/source/genotoxicity)). The organs that will be targeted are the liver ([hepatotoxicity](/source/hepatotoxicity)), the kidneys ([nephrotoxicity](/source/nephrotoxicity)) and the lungs ([pneumotoxicity](/source/pneumotoxicity)). MCT falls into [Category 3](/source/Toxicity_category_rating) toxicity for oral ingestion and Category 2 toxicity for [carcinogen](/source/carcinogen)icity according to the [European Chemicals Agency](/source/European_Chemicals_Agency) (ECHA).[{{Cite journal|last1=Suparmi|first1=Suparmi|last2=Wesseling|first2=Sebastiaan|last3=Rietjens|first3=Ivonne M. C. M.|date=2020-09-01|title=Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach|url=https://doi.org/10.1007/s00204-020-02798-z|journal=Archives of Toxicology|language=en|volume=94|issue=9|pages=3281–3295|doi=10.1007/s00204-020-02798-z|issn=1432-0738|pmc=7415757|pmid=32518961|bibcode=2020ArTox..94.3281S }}]
Studies concluded that the ingestion of MCT will cause centrilobular [necrosis](/source/necrosis), pulmonary [fibrosis](/source/fibrosis) and increase in [blood urea nitrogen](/source/blood_urea_nitrogen). These conclusions are based on the models that were used during these studies as these effects were caused in rats instead of humans. During the studies it was also concluded that mice are more resilient to MCT than rats, meaning that more mice survived the experiments than rats.[{{Cite journal|last1=Suparmi|first1=Suparmi|last2=Wesseling|first2=Sebastiaan|last3=Rietjens|first3=Ivonne M. C. M.|date=2020-09-01|title=Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach|url=https://doi.org/10.1007/s00204-020-02798-z|journal=Archives of Toxicology|language=en|volume=94|issue=9|pages=3281–3295|doi=10.1007/s00204-020-02798-z|issn=1432-0738|pmc=7415757|pmid=32518961|bibcode=2020ArTox..94.3281S }}][{{Cite journal|last1=Molteni|first1=Agostino|last2=Ward|first2=William F.|last3=Ts’ao|first3=Chung-hsin|last4=Solliday|first4=Norman H.|date=1989-01-01|title=Monocrotaline pneumotoxicity in mice|url=https://doi.org/10.1007/BF02899076|journal=Virchows Archiv B|language=en|volume=57|issue=1|pages=149–155|doi=10.1007/BF02899076|pmid=2570481|s2cid=29465237|issn=0340-6075|url-access=subscription}}][{{Cite journal|last1=Roth|first1=R. A.|last2=Dotzlaf|first2=L. A.|last3=Baranyi|first3=B.|last4=Kuo|first4=C. -H.|last5=Hook|first5=J. B.|date=1981-09-15|title=Effect of monocrotaline ingestion on liver, kidney, and lung of rats|url=https://dx.doi.org/10.1016/0041-008X%2891%2990223-2|journal=Toxicology and Applied Pharmacology|language=en|volume=60|issue=2|pages=193–203|doi=10.1016/0041-008X(91)90223-2|pmid=6792747|bibcode=1981ToxAP..60..193R |issn=0041-008X|url-access=subscription}}]
== Biosynthesis of monocrotaline ==
The [biosynthesis](/source/biosynthesis) of MCT involves [condensation](/source/condensation_reaction) of monocrotalic acid (MCA), which is derived from [L-isoleucine](/source/Isoleucine), and [retronecine](/source/retronecine), which is derived from [putrescine](/source/putrescine).
MCA is formed from L-isoleucine and a [synthon](/source/synthon) for [propionate](/source/propionate) of uncertain origin.[{{cite journal |title= Pyrrolizidine alkaloids. Biosynthesis of monocrotalic acid, the necic acid component of monocrotaline |last1= Robins |first1= David J. |last2= Bale |first2= Nicholas M. |last3= Crout |first3= David H. G. |year= 1974 |journal= Journal of the Chemical Society, Perkin Transactions 1 |issue= 18 |pages= 2082–2086 |doi= 10.1039/p19740002082 |pmid= 4473457 }}]
Retronecine is synthesized from [L-arginine](/source/Arginine) via a multi-step pathway involving [putrescine](/source/putrescine) and [spermidine](/source/spermidine) intermediates:
alt=Biosynthesis route of retronecine in plants.|none|thumb|547x547px|Biosynthesis route of retronecine in plants.
Putrescine is converted to [spermidine](/source/spermidine) by addition of a [propylamino](/source/propylamine) group from decarboxylated [''S''-adenosylmethioninamine](/source/S-Adenosylmethioninamine) (4: [spermidine synthase](/source/spermidine_synthase)). Spermidine and another molecule of [putrescine](/source/putrescine) react to form the symmetric homospermidine with loss of [1,3-diaminopropane](/source/1%2C3-diaminopropane) (5: [homospermidine synthase](/source/homospermidine_synthase)).
Oxidation (likely catalysed by 6: copper-dependent diamine oxidases) to 4,4’-iminodibutanal results into the [cyclization](/source/Cyclic_compound) of pyrrolizidine-1-carbaldehyde, which is reduced to 1-hydroxymethyl pyrrolizidine (likely catalysed by 7: [alcohol dehydrogenase](/source/alcohol_dehydrogenase)). To form the final product retronecine, 1-hydroxymethyl pyrrolizidine is desaturated and [hydroxylated](/source/Hydroxylation) respectively by unknown enzymes.[{{Cite journal|last1=Schramm|first1=Sebastian|last2=Köhler|first2=Nikolai|last3=Rozhon|first3=Wilfried|date=2019-01-30|title=Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants|journal=Molecules|volume=24|issue=3|pages=498|doi=10.3390/molecules24030498|pmid=30704105|pmc=6385001|issn=1420-3049|doi-access=free}}]
MCA and retronecine are then condensed to form MCT via an unknown mechanism:
alt=Biosynthesis of monocrotaline in plants.|none|thumb|497x497px|Biosynthesis of monocrotaline in plants.
== Biotransformation of monocrotaline ==
MCT is [detoxified](/source/Detoxification) in [rat](/source/rat)s by the liver via divergent [biotransformation](/source/biotransformation) reactions. These reactions proceed as follows:
alt=Biotransformation route of monocrotaline in rats.|none|thumb|542x542px|Biotransformation route of monocrotaline in rats.
In Rats, MCT is first oxidised by the biotransformation enzyme [cytochrome P450](/source/cytochrome_P450) (CYP) to form dehydro MCT. In this phase 1 reaction a double carbon-carbon bond is introduced out of a single carbon-carbon bond.
After the phase 1 reaction, the oxidised intermediate can either undergo hydrolysis to form monocrotalic acid and dihydropyrolizine or perform group transfer with [glutathione](/source/glutathione) to form MCA and a glutathione-conjugated dihydropyrolizine (GS-conjugation). These metabolites are more hydrophilic than MCT and could therefore be more easily excreted by the kidneys, which results in less exposure from MCT to the liver. The phase 2 reactions are thus classified as the detoxifying reactions during the biotransformation of MCT in rats.
During the phase 2 reactions, dehydro MCT can react with nucleophilic biological macromolecules (NuS) which is a toxic intermediate. Addition of such molecules may result into [Cytotoxicity](/source/Cytotoxicity). Dehydro MCT may also undergo further toxification after hydrolysis, as dihydropyrolizine can be further oxidized to 7-dihydro-1-hydroxymethyl-5H-pyrrolizine (DHP). This intermediate can bind to DNA which may cause [Genotoxicity](/source/Genotoxicity).[{{Cite journal |last1=Pitanga |first1=Bruno |last2=Nascimento |first2=Ravena |last3=Silva |first3=Victor Diogenes |last4=Costa |first4=Silvia |date=2012 |title=The Role of Astrocytes in Metabolism and Neurotoxicity of the Pyrrolizidine Alkaloid Monocrotaline, the Main Toxin of Crotalaria retusa |journal=Frontiers in Pharmacology |volume=3 |page=144 |doi=10.3389/fphar.2012.00144 |pmid=22876233 |pmc=3411086 |issn=1663-9812|doi-access=free }}]
Note that the biotransformation routes may differ based on the studied organism.[{{Cite journal|last1=Szymanski|first1=Edward S.|last2=Little|first2=Nancy A.|last3=Kritchevsky|first3=David|date=1981|title=Phospholipid metabolism in livers of young and old fisher 344 and Sprague-Dawley rats|url=http://dx.doi.org/10.1016/0531-5565(81)90041-3|journal=Experimental Gerontology|volume=16|issue=2|pages=163–169|doi=10.1016/0531-5565(81)90041-3|pmid=7286096|s2cid=9094511|issn=0531-5565|url-access=subscription}}]
== Mechanism of action ==
MCT aggregates on and activates the [calcium-sensing receptor](/source/calcium-sensing_receptor) (CaSR) of pulmonary artery [endothelial cells](/source/endothelial_cells) to trigger endothelial damage and, ultimately, induces [pulmonary hypertension](/source/pulmonary_hypertension). MCT binds to the extracellular domain of the CaSR (calcium-sensing receptor). Thereby, the assembly of CaSR is enhanced and triggers the mobilisation of calcium signalling, and damages pulmonary artery endothelial cells. In addition, MCT strengthens this effect by binding to the [bone morphogenetic protein receptor type II](/source/BMPR2) (BMPR2), which is a [transmembrane receptor](/source/Cell_surface_receptor). BMPR2 inhibition occurs which in turn induces a blockade of BMPR1 receptor activation via [phosphorylation](/source/phosphorylation). Inhibiting this process disturbs cell differentiation processes and ossification. Interference with these receptors induce pulmonary arterial hypertension.
alt=Monocrotaline: mechanism of action.|thumb|Monocrotaline: schematic mechanism of action.
[MAPK](/source/MAPK) is a mitogen activated protein kinase that gets activated upon BMPR2 activation. The protein kinase in turn phosphorylates p38 via a reinforced cascade of intracellular signals. It also activates p21 which has a regulating role in the cell cycle. However, MCT administration inhibits this process via a blockade of BMPR2. [Cytokine](/source/Cytokine)s such as [TNF-α](/source/TNF-%CE%B1) are released which cause activation of [inflammation](/source/inflammation) mechanisms, attracting [neutrophil](/source/neutrophil)s among others. Furthermore, inducible [nitric oxide synthase](/source/nitric_oxide_synthase)s (iNOS) are upregulated upon MCT induced cellular stress, whereas [endothelial NOS](/source/endothelial_NOS) (eNOS) gets downregulated. The cytokine TGF-β (also released by macrophages via chemotaxis during inflammation reactions in a positive feedback loop with TNF-α) is a transforming growth factor that is upregulated as a result of iNOS increase, contributing to pulmonary artery proliferation. Increased levels of iNOS also stimulate [caspase-3](/source/Caspase_3) activity which increases [apoptosis](/source/apoptosis) levels.[{{Cite journal|last1=Ahmed|first1=Lamiaa A.|last2=Obaid|first2=Al Arqam Z.|last3=Zaki|first3=Hala F.|last4=Agha|first4=Azza M.|date=2014-10-01|title=Naringenin adds to the protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in rats: Favorable modulation of oxidative stress, inflammation and nitric oxide|url=https://www.sciencedirect.com/science/article/pii/S092809871400195X|journal=European Journal of Pharmaceutical Sciences|language=en|volume=62|pages=161–170|doi=10.1016/j.ejps.2014.05.011|pmid=24878387|issn=0928-0987|url-access=subscription}}]
== See also ==
* [Oxidative stress](/source/Oxidative_stress)
== References ==
{{Reflist}}
Category:Pyrrolizidine alkaloids
Category:Lactones
Category:Vicinal diols
Category:Tertiary alcohols
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Adapted from the Wikipedia article [Monocrotaline](https://en.wikipedia.org/wiki/Monocrotaline) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Monocrotaline?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.