Phorbol

Phorbol is a natural product found in many plants, especially those of the Euphorbiaceae and Thymelaeaceae families. Phorbol and phorbol esters are the active constituents of the highly toxic New World tropical manchineel tree (Hippomane mancinella). It is very soluble in most polar organic solvents, as well as in water. In the manchineel, this leads to an additional exposure risk during rain, where liquid splashing from an undamaged tree may also be injurious. Contact with the tree or consumption of its fruit can lead to symptoms such as severe pain and swelling. The purging croton, Croton tiglium, is the source of croton oil from which phorbol was initially isolated. Its seeds and oil have been used for hundreds of years in traditional medicine, generally as a purgative, and the seeds were mentioned in Chinese herbal texts 2000 years ago. The purgative effects of the oil are largely attributed to the high percentage of phorbol esters contained in the oil. Phorbol was isolated from C. tiglium seeds in 1934. ==Mechanism of action==

Phorbol derivatives work primarily by interacting with protein kinase C (PKC), although they can interact with other phospholipid membrane receptors. The esters bind to PKC in a similar way to its natural ligand, diacylglycerol, and activate the kinase. Diacylglycerol is degraded quickly by the body, allowing PKC to be reversibly activated. When phorbol esters bind to the receptor, they are not degraded as efficiently by the body, leading to constitutively active PK. Symptoms can include edema and pain, especially to the skin and mucous membranes. While phorbol itself does not have irritant activity, nearly all phorbol esters are highly irritant, with a wide range of half-maximal inhibitory concentration (IC50) values. The median lethal dose (LD50) of phorbol esters for male mice was found to be about 27 mg/kg, with the mice showing hemorrhage and congestion of pulmonary blood vessels, as well as lesions throughout the body. ==Total synthesis==

A total synthesis of enantiopure phorbol was developed in 2015. While this synthesis will not replace natural isolation products, it will enable researchers to create phorbol analogs for use in research, especially creating phorbol derivatives that can be evaluated for anti-cancer activity. : ==Uses in biomedical research==

Because of their mechanism of action, phorbol esters can be used to study tumor proliferation and pain response. TPA is most commonly used in the laboratory to induce a cellular response. For example, TPA can be used to measure response to pain and test compounds that may mitigate the inflammatory response. TPA and other phorbol esters can also be used to induce tumor formation and to study mechanism of action.--> Possible and purported medicinal uses The phorbol ester tigilanol tiglate reportedly has in vitro anti-cancer, antiviral, and antibacterial activities.--> == References ==