Tetrahydrocurcumin: Characterization and Beneficial Effects on Human Diseases

General Description

Tetrahydrocurcumin, a metabolite of curcumin, exhibits enhanced chemical stability and superior oral absorption compared to its parent compound. It is an off-white compound lacking the double bonds of curcumin, which contributes to its distinct properties and lower toxicity. Tetrahydrocurcumin has potent antioxidant capabilities, effectively combating diseases linked to oxidative stress, and it enhances the activity of antioxidant enzymes. Despite relatively poor overall bioavailability in rats, its safety profile is strong, with no toxicity reported at high doses. Its unique molecular characteristics allow for flexible enzyme interactions, suggesting potential therapeutic applications in various human diseases.

Figure 1. Tetrahydrocurcumin

Characterization

Chemical Characteristics and Stability

Tetrahydrocurcumin, a notable metabolite of curcumin, was first identified by Holder et al. in 1978 through studies involving tritium-labeled curcumin. Its chemical structure is similar to curcumin but differs in lacking the double bonds within its central seven-carbon chain. This structural difference results in tetrahydrocurcumin being an off-white compound, unlike curcumin, which is characterized by its vibrant color due to the presence of α, β-unsaturated carbonyl moiety. Tetrahydrocurcumin is primarily isolated in conjugated forms within various tissues, such as the liver, intestines, kidneys, and brain, in addition to being detected unconjugated in the plasma of mice. Studies confirm that tetrahydrocurcumin exhibits superior chemical stability compared to curcumin, particularly in phosphate buffers and aqueous solutions. The terminal half-life of tetrahydrocurcumin is also significantly longer than that of curcumin, demonstrating its greater stability in biological environments. ¹

Oral Absorption and Metabolism

Tetrahydrocurcumin not only occurs naturally in several plant roots but can also be synthetically produced through the hydrogenation of curcumin. Its superior solubility and stability compared to curcumin are well-documented. In vivo studies have shown that tetrahydrocurcumin exhibits better oral absorption and higher levels of free tetrahydrocurcumin in liver and serum after daily oral administration, surpassing the absorption levels of curcumin. When administered through various routes, including oral gavage and intramuscular injection, tetrahydrocurcumin consistently demonstrates elevated plasma levels of the compound. Despite its improved gastrointestinal absorption, tetrahydrocurcumin's overall oral bioavailability remains relatively poor in rats, with most of the compound being excreted through non-renal routes. This highlights tetrahydrocurcumin's potential advantages in terms of stability and absorption, albeit with some limitations in bioavailability. ²

Beneficial Effects on Human Diseases

Renal Protective

Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-2′-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2′-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.¹

Antioxidant Properties

Tetrahydrocurcumin has many more desirable biological and pharmacological properties than curcumin. It has been recognized as a superior antioxidant that is responsible for its chemo-preventive efficacy against various diseases, including hypertension, atherosclerosis, diabetes, neurotoxicity, cardiovascular disease, hepatotoxicity, and liver fibrosis. Curcumin also acts as an anti-oxidant; it may elicit pro-oxidant effects at higher dosages due to its phenyl hydroxyl groups, phenyl methoxy groups, and α, β-unsaturated carbonyl moiety, as well as the ability to modify enzyme activity that results in reactive oxygen species (ROS) formation. In contrast to curcumin, tetrahydrocurcumin does not generate ROS because it lacks conjugated bonds in the central seven-carbon chain. The anti-oxidative mechanism of tetrahydrocurcumin has been proposed to be due to its ability to scavenge radicals by phenyl hydroxyl groups; more importantly, though, its activity involves the cleavage of the C-C bond at the active methylene carbon between the two carbonyls in the β-diketone moiety during oxidation. This cleavage results in the production of o-methoxy phenol products that also act as antioxidants. Another anti-oxidative mechanism of tetrahydrocurcumin appears to be its ability to increase the activities of anti-oxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase; tetrahydrocurcumin was shown to be more potent than curcumin in several corresponding in vivo studies.²

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