Chemistry:Rottlerin

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Short description: Chemical compound
Rottlerin
Rottlerin.svg
Clinical data
Other namesMallotoxin
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC30H28O8
Molar mass516.546 g·mol−1
3D model (JSmol)

Rottlerin (mallotoxin) is a polyphenol natural product isolated from the Asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.[1]

Effects

Uncoupler of oxidative phosphorylation

Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation.[2][3][4]

Potassium channel opener

Rottlerin is a potent large conductance potassium channel (BKCa++) opener.[5] BKCa++ is found in the inner mitochondrial membrane of cardiomyocytes.[6] Opening these channels is beneficial for post-ischemic changes in vasodilation.[7] Other BKCa++ channel openers are reported to limit the mitochondrial calcium overload due to ischemia.[8][9] Rottlerin is also capable of reducing oxygen radical formation.[1]

Other BKCa++ channel openers (NS1619, NS11021 and DiCl-DHAA) have been reported to have cardio-protective effects after ischemic-reperfusion injury.[9][10][11] There were reductions in mitochondrial Ca++ overload, mitochondrial depolarization, increased cell viability and improved function in the whole heart.[9][10][11]

Mallotoxin is also a hERG potassium channel activator.[12]

Role in cardioplegia reperfusion

Clements et al.[5] reported that rottlerin improves the recovery of isolated rat hearts perfused with buffer after cold cardioplegic arrest. A majority of patients recover but some develop a cardiac low-output syndrome attributable in part to depressed left ventricular or atrial contractility, which increases chance of death.[5]

Contractility and vascular effects

Rottlerin increases in isolated heart contractility independent of its vascular effects, as well as enhanced perfusion through vasomotor activity.[5] The activation of BKCa++ channels by rottlerin relaxes coronary smooth muscle and improves myocardial perfusion after cardioplegia.[5]

Myocardial stunning is associated with oxidant radical damage and calcium overload.[5] Contractile abnormalities can occur through oxidant-dependent damage and also through calcium overload in the mitochondria resulting in mitochondrial damage.[13][14][15] BKCa++ channels reside in the inner mitochondrial membrane[6] and their activation is proposed to increase K+ accumulation in mitochondria.[8][9] This limits Ca2+ influx into mitochondria, reducing mitochondrial depolarization and permeability transition pore opening.[8][9] This may result in less mitochondrial damage and therefore greater contractility since there is a decrease in apoptosis compared to no stimulation of BKCa++ channels.[5]

Akt activation

Rottlerin also enhances the cardioplegia-induced phosphorylation of Akt on the activation residue Thr308.[5] Akt activation modulates mitochondrial depolarization and the permeability transition pore.[16][17] Clements et al.[5] found that Akt functions downstream of the BKCa++ channels and its activation is considered beneficial after ischemic-reperfusion injury. It is unclear what the specific role of Akt may play in modulating of myocardial function after rottlerin treatment of cardioplegia.[5] More research needs to be done to examine if Akt is necessary to improve cardiac function when rottlerin is administered.[5]

Antioxidant properties

The antioxidant properties of rottlerin have been demonstrated but it is unclear whether the effects are because of BKCa++ channel opening or an additional mechanism of rottlerin.[1][5][18] There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.[5]

Ineffective PKCδ selective inhibitor

Rottlerin has been reported to be a PKCδ inhibitor.[19] PKCδ has been implicated in depressing cardiac function and cell death after ischemia-reperfusion injury as well as promoting vascular smooth muscle contraction and decreasing perfusion.[5] However, the role of rottlerin as a specific PKCδ inhibitor has been questioned. There have been several studies using rottlerin as a PKCδ selective inhibitor based on in vitro studies, but some studies showed it did not block PKCδ activity and did block other kinase and non-kinase proteins in vitro.[1][20][21] Rottlerin also uncouples mitochondria at high doses and results in depolarization of the mitochondrial membrane potential.[1] It was found to reduce ATP levels, activate 5'-AMP-activated protein kinase and affect mitochondrial production of reactive oxygen species (ROS).[1][6][22] It is difficult to say that rottlerin is a selective inhibitor of PKCδ since there are biological and biochemical processes that are PKCδ –independent that may affect outcomes.[1][5][6][22] A proposed mechanism of why rottlerin was found to inhibit PKCδ is that it decreased ATP levels and can block PKCδ tyrosine phosphorylation and activation.[1]

Sources

The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia.[19] The fruit of this tree is covered with a red powder called kamala, and is used locally to make dye for textiles, syrup and used as an old remedy for tape-worm, because it has a laxative effect.[23] Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.[24]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta". Trends in Pharmacological Sciences 28 (9): 453–458. September 2007. doi:10.1016/j.tips.2007.07.003. PMID 17692392. 
  2. ↑ "Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation". The Journal of Biological Chemistry 276 (41): 37986–37992. October 2001. doi:10.1074/jbc.M105073200. PMID 11498535. 
  3. ↑ "Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation". Endocrinology 143 (10): 3884–3896. October 2002. doi:10.1210/en.2002-220259. PMID 12239100. 
  4. ↑ "Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C". Cancer Research 63 (16): 5118–5125. August 2003. PMID 12941843. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 "Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts". Circulation 124 (11 Suppl): S55–S61. September 2011. doi:10.1161/CIRCULATIONAHA.110.012112. PMID 21911819. 
  6. ↑ 6.0 6.1 6.2 6.3 "Activation of the BK (SLO1) potassium channel by mallotoxin". The Journal of Biological Chemistry 280 (35): 30882–30887. September 2005. doi:10.1074/jbc.M505302200. PMID 15998639. 
  7. ↑ "Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation". The Journal of Heart and Lung Transplantation 28 (10): 1094–1101. October 2009. doi:10.1016/j.healun.2009.06.011. PMID 19782293. 
  8. ↑ 8.0 8.1 8.2 "Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes". American Journal of Physiology. Heart and Circulatory Physiology 293 (1): H307–H313. July 2007. doi:10.1152/ajpheart.00789.2006. PMID 17351070. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "Mitochondrial Ca2+-activated K+ channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A". Circulation 111 (2): 198–203. January 2005. doi:10.1161/01.cir.0000151099.15706.b1. PMID 15623543. 
  10. ↑ 10.0 10.1 "Activation of big conductance Ca(2+)-activated K (+) channels (BK) protects the heart against ischemia-reperfusion injury". Pflügers Archiv 457 (5): 979–988. March 2009. doi:10.1007/s00424-008-0583-5. PMID 18762970. 
  11. ↑ 11.0 11.1 "A novel opener of large-conductance Ca2+ -activated K+ (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel". Journal of Pharmacological Sciences 108 (1): 135–139. September 2008. doi:10.1254/jphs.08150sc. PMID 18758135. 
  12. ↑ "Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator". The Journal of Pharmacology and Experimental Therapeutics 319 (2): 957–962. November 2006. doi:10.1124/jpet.106.110593. PMID 16928897. 
  13. ↑ "Molecular and cellular mechanisms of myocardial stunning". Physiological Reviews 79 (2): 609–634. April 1999. doi:10.1152/physrev.1999.79.2.609. PMID 10221990. 
  14. ↑ "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2". Circulation 104 (25): 3158–3167. December 2001. doi:10.1161/hc5001.100039. PMID 11748117. 
  15. ↑ "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1". Circulation 104 (24): 2981–2989. December 2001. doi:10.1161/hc4801.100038. PMID 11739316. 
  16. ↑ "Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis". Cardiovascular Research 88 (1): 7–15. October 2010. doi:10.1093/cvr/cvq206. PMID 20562423. 
  17. ↑ "The role of mitochondria in protection of the heart by preconditioning". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1767 (8): 1007–1031. August 2007. doi:10.1016/j.bbabio.2007.05.008. PMID 17631856. 
  18. ↑ "Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels". American Journal of Physiology. Heart and Circulatory Physiology 293 (3): H1400–H1407. September 2007. doi:10.1152/ajpheart.00198.2007. PMID 17513497. 
  19. ↑ 19.0 19.1 "Rottlerin, a novel protein kinase inhibitor". Biochemical and Biophysical Research Communications 199 (1): 93–98. February 1994. doi:10.1006/bbrc.1994.1199. PMID 8123051. 
  20. ↑ "Specificity and mechanism of action of some commonly used protein kinase inhibitors". The Biochemical Journal 351 (Pt 1): 95–105. October 2000. doi:10.1042/0264-6021:3510095. PMID 10998351. 
  21. ↑ "Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation". The Journal of Biological Chemistry 276 (41): 37986–37992. October 2001. doi:10.1074/jbc.M105073200. PMID 11498535. 
  22. ↑ 22.0 22.1 "Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1763 (1): 25–38. January 2006. doi:10.1016/j.bbamcr.2005.10.007. PMID 16364465. 
  23. ↑ "Kamala dye as an anthelmintic". Proceedings of the Indian Academy of Sciences 26 (3): 178–181. 1947. doi:10.1007/BF03170871. 
  24. ↑ "Kamala--the national flower of India--its ancient history and uses in Indian medicine". Indian Journal of History of Science 11 (2): 125–132. November 1976. PMID 11610202. 



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