Perspective paperOleanolic acid and ursolic acid: Research perspectives
Section snippets
“Dose differentiates a poison from a remedy”
Paracelsus pointed out in the 16th century that “All substances are poisons; there is none which is not poison. The right dose differentiates a poison from a remedy”. Like many herbal ingredients, the selection of the appropriate dose of these triperpenoids is critical. Although these triterpenoids are relatively safe, toxicities do occur in certain circumstances. For example, low-doses of oleanolic acid are hepatoprotective, while the high-dose could produce cholestasis and hepatotoxicity.
Chemical modifications of oleanolic acid
A major advancement during the past 10 years is the synthesis of derivatives from the natural triterpenoids such as oleanolic acid. For example, the oleanolic acid derivative 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) has been generated, which is more potent than the parent compound in anti-inflammatory actions and more effective in inhibiting iNOS and COX2 as a basis of its anti-inflammatory effects (Suh et al., 1998). Other synthetic derivatives, such as carbenoxone and uvaol
Mixtures and chemical interactions
One major feature of the traditional medicine is the use of herb mixtures. Modern pure compound research is necessary to advance our knowledge of their structure–activity relationships and the mechanism of their biological actions. However, the mixtures of these active ingredients are more effective than a single compound in producing desired biological effects, and are the common practice in health care and clinical treatments. For example, oleanolic acid has been used in the formula of
Hepatoprotection perspectives
Oleanolic acid and ursolic acid are well known for their hepatoprotective effects for both acute chemically induced liver injury and chronic liver fibrosis and cirrhosis (Liu, 1995). They are still used alone or in combination with other hepatoprotective ingredients as oral medications. The beneficial effects of these triterpenoids on the liver could be due to their anti-oxidant and anti-inflammatory actions, and their effects on drug-metabolizing enzymes. These triterpenoids are effective
Chemotherapy perspectives
Oleanolic acid and ursolic acid have been shown to act at various stages of tumor development to inhibit tumor initiation and promotion, as well as to induce tumor cell differentiation and apoptosis. In the two-stage mouse skin carcinogenesis model, the protection of oleanolic acid against 12-O-teradecanoyl phorbol-13-acetate promoted carcinogenesis is associated with inhibition of aberrant gene expression (Oguro et al., 1998). Oleanolic acid derivatives are also effective for acute myeloid
Signal transduction pathways
The advance of molecular biology techniques has greatly helped our understanding of these triterpenoids. More and more sophisticated studies have been directed at the molecular levels to understand the mechanism of their biological effects. For example, the involvement of MAP kinase pathways (JNK) has been demonstrated in oleanolic acid derivative induced apoptosis in lung cancer cells and in leukemia cells (Zou et al., 2004). The induction of the phase-2 enzymes such as heme oxygenase 1 and
Other pharmacological effects
A variety of novel pharmacological effects produced by these triterpenoids have been reported, including their beneficial effects on cardiovascular systems (Somova et al., 2003), interaction with cytochrome P450s (Kim et al., 2004), protection against kainate-induced excitotoxicity in rat hippocampal neurons and immunomodulatory effects, as well as its effects on intracellular redox balance and osteoclast formation. The monoclonal antibody against oleanolic acid has also been generated. These
Acknowledgements
The author thanks critical review by Drs. Wei Qu, Yaxiong Xie and Larry Keefer for their critical comments on this commentary. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services.
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