Phorbol Esters: Structure, Biological Activity, And Toxicology

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International Journal of Toxicology, 26:279–288, 2007
Copyright c American College of Toxicology
ISSN: 1091-5818 print / 1092-874X online
DOI: 10.1080/10915810701464641

Phorbol Esters: Structure, Biological Activity, and Toxicity in Animals
Gunjan Goel, Harinder P. S. Makkar, George Francis, and Klaus Becker
Institute for Animal Production in the Tropics and Subtropics, University of Hohenheim,
Stuttgart, Germany

Phorbol esters are the tetracyclic diterpenoids generally known for their tumor promoting activity. The phorbol esters mimic the action of diacyl glycerol (DAG), activator of protein kinase C, which regulates different signal transduction pathways and other cellular metabolic activities. They occur naturally in many plants of the family Euphorbiacaeae and Thymelaeaceae. The biological activities of the phorbol esters are highly structure specific. The phorbol esters, even at very low concentrations, show toxicological manifestations in animals fed diets containing them. This toxicity limits the use of many nutritive plants and agricultural by-products containing phorbol esters to be used as animal feed. Therefore, various chemical and physical treatments have been evaluated to extract or inactivate phorbol esters so that seed meals rich in proteins could be used as feed resources. However, not much progress has been reported so far. The detoxifying ability has also been reported in some molluscs and in liver homogenate of mice. Besides, possessing antinutritional and toxic effects, few derivatives of the phorbol esters are also known for their antimicrobial and antitumor activities. The molluscicidal and insecticidal properties of phorbol esters indicate its potential to be used as an effective biopesticide and insecticide. Keywords

Detoxification, Jatropha curcas, Phorbol Esters, Protein
Kinase C, Tumor

The term ‘phorbol’ is used to describe the family of naturally occurring compounds that can be referred to as tigliane diterpenes (Evans 1986). Phorbol esters are defined as “polycyclic compounds in which two hydroxyl groups on neighboring carbon atoms are esterified to fatty acids.” Several plants, such as Sapium indicum, S. japonicum, Euphorbia frankiana,
E. cocrulescence, E. ticulli, Croton spareiflorus, C. tigilium, C. ciliatoglandulifer, Jatropha curcas, Excoecaria agallocha, and
Homalanthus nutans, are reported to contain the toxic phorbols
(Beutler et al. 1989). Among these plants, J. curcas has also been reported to possess other potential toxic compounds such as
Received 17 January 2007; accepted 16 April 2007.
Address correspondence to Dr. H. P. S. Makkar, Institute for Animal
Production in the Tropics and Subtropics (480b), Department of Aquaculture, University of Hohenheim, 70593 Stuttgart, Germany. E-mail: curcin and hydrocyanic acid (CRC 1977). There are several other plants that contain different derivatives of phorbol and diterpenes, such as crotonogyne, crytogonone, dimorphocalyx, duvigneaudia, fahrenheitia, maprounea, and plagiostyles (Beutler et al. 1989). Indirect exposure to such plants takes place through consumption of animal products polluted with toxic phorbol esters, such as honey collected by bees (Sosath, Ott, and Hecker
1988), meat (fish or game) captured in primitive hunting that is rendered toxic by plant materials, and meat and milk produced from the animals that feed on diets contaminated with these toxic components (Zayed et al. 1998). The active phorbol ester, TPA
(4ß-12-O-tetradecanoylphorbol-13-acetate), was first found in the croton plant, a shrub found in Southeast Asia. The interaction of phorbol ester with protein kinase C (PKC) affects activities of several enzymes, biosynthesis of protein, DNA, polyamines, cell differentiation processes, and gene expression. The toxicity of phorbol esters has been reported on feeding plants containing these esters to various animal models, such as goat, mice, rat, and fish. The molluscicidal activity has been