Antioxidant activity of curcumin and related compounds

THE importance of prostaglandins in inflammation has been emphasized by the discovery that aspirin-like anti-inflammatory drugs inhibit their synthesis1–3. The anti-inflammatory and anti-pyretic effects of this group of drugs could be explained on this basis1, but their analgesic properties could not, then, be firmly linked to inhibition of prostaglandin synthesis. This was because the only subjective effect reported on intradermal injection of prostaglandin was a sensation of warmth and a slight itching*, and on the blister base PGE2 (up to 100 µg/ml.) failed to produce pain5. Several reports now describe the pain-producing activity of prostaglandins infused i.v. and injected intramuscularly6–8 in man. Collier and Schneider have shown that PGE1 is the most powerful agent in producing writhing responses in mice9. Vane1 suggested that rabbit aorta contracting substance (RCS)10 which may be the unstable cyclic peroxide intermediate in the biosynthesis of prostaglandins11, may be involved in the production of pain in inflammation. I tried to test this hypothesis by comparing the pain producing activity of fatty acid hydroperoxides with that of high concentrations of acetylcholine, bradykinin, histamine and PGE1 on intradermal injection in man. The intensity of the pain induced by the hydroperoxides was greater than that induced by the other agonists but for all except PGE1 the pain was transitory. On testing subdermal infusions to mimic the continuous release of an endogenous mediator of pain, two important properties of E-type prostaglandins were revealed. First, they increase the pain sensitivity to chemical and mechanical stimulation. Second, their effects are cumulative and depend not only on their concentrations but also on the time of exposure. The term “pain” is used to denote the overt pain evoked chemically during the infusions; hyperalgesia is used when pain was elicited only by applying slight pressure on the infusion area. Studies were carried out in five male volunteers each of whom received a full explanation of the nature of the experiment before giving his consent. The experiments were double blind.

Prostaglandins, aspirin-like drugs and analgesia.

Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited.

https://clincancerres.aacrjournals.org/content/clincanres/7/7/1894.full.pdf

Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer

The uptake, distribution and excretion of curcumin in Sprague-Dawley rats has been studied. When administered orally in a dose of 1 g/kg, curcumin was excreted in the faeces to about 75%, while negligible amounts of curcumin appeared in the urine. Measurements of blood plasma levels and biliary excretion showed that curcumin was poorly absorbed from the gut. No apparent toxic effects were seen after doses of up to 5 g/kg. When intravenously injected or when added to the perfusate of the isolated liver, curcumin was actively transported into bile, against concentration gradients of several hundred times. The major part of the drug was however metabolized. In suspensions of isolated hepatocytes or liver microsomes 90% of the added curcumin was metabolized within 30 min. In view of the poor absorption, rapid metabolism and excretion of curcumin, it is unlikely that substantial concentrations of curcumin occur in the body after ingestion.

A study on the fate of curcumin in the rat

Curcumin, the yellow pigment in turmeric, prevents malignancies in the intestinal tract of rodents. It is under clinical evaluation as a potential colon cancer chemopreventive agent. The systemic bioavailability of curcumin is low, perhaps attributable, at least in part, to metabolism. Indirect evidence suggests that curcumin is metabolized in the intestinal tract. To investigate this notion further, we explored curcumin metabolism in subcellular fractions of human and rat intestinal tissue, compared it with metabolism in the corresponding hepatic fractions, and studied curcumin metabolism in situ in intact rat intestinal sacs. Analysis by high-performance liquid chromatography, with detection at 420 or 280 nm, permitted characterization of curcumin conjugates and reduction products. Chromatographic inferences were corroborated by mass spectrometry. Curcumin glucuronide was identified in intestinal and hepatic microsomes, and curcumin sulfate, tetrahydrocurcumin, and hexahydrocurcumin were found as curcumin metabolites in intestinal and hepatic cytosol from humans and rats. The extent of curcumin conjugation was much greater in intestinal fractions from humans than in those from rats, whereas curcumin conjugation was less extensive in hepatic fractions from humans than in those from rats. The curcumin-reducing ability of cytosol from human intestinal and liver tissue exceeded that observed with the corresponding rat tissue by factors of 18 and 5, respectively. Curcumin sulfate was identified in incubations of curcumin with intact rat gut sacs. Curcumin was sulfated by human phenol sulfotransferase isoenzymes SULT1A1 and SULT1A3. Equine alcohol dehydrogenase catalyzed the reduction of curcumin to hexahydrocurcumin. The results show that curcumin undergoes extensive metabolic conjugation and reduction in the gastrointestinal tract and that there is more metabolism in human than in rat intestinal tissue. The pharmacological implications of the intestinal metabolism of curcumin should be taken into account in the design of future chemoprevention trials of this dietary constituent.

/pdf/metabolism-of-the-cancer-chemopreventive-agent-curcumin-in-2i9mydoxkj.pdf

S.C. Sharma

Papers

Two substituted bibenzyls and a dihydrophenanthrene from Cymbidium Aloifolium

Lipid peroxide formation in experimental inflammation.

Prevention of renal ischemia-reperfusion-induced injury in rats by picroliv.

Picroliv preconditioning protects the rat liver against ischemia–reperfusion injury

Alkaloids and terpenoids of Ancistrocladus heyneanus, Sagittaria sagitifolia, Lyonia formosa and Hedychium spicatum☆