Clinical data | |
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Other names | Mallotoxin |
Identifiers | |
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CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard ( EPA) | |
ECHA InfoCard | 100.001.270 |
Chemical and physical data | |
Formula | C30H28O8 |
Molar mass | 516.546 g·mol−1 |
3D model ( JSmol) | |
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Rottlerin (mallotoxin) is a polyphenol natural product isolated from the Asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology. [1]
Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation. [2] [3] [4]
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]
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]
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]
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]
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]
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]
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]
Clinical data | |
---|---|
Other names | Mallotoxin |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard ( EPA) | |
ECHA InfoCard | 100.001.270 |
Chemical and physical data | |
Formula | C30H28O8 |
Molar mass | 516.546 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]
Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation. [2] [3] [4]
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]
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]
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]
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]
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]
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]
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]