Metabolism of caffeic acid

Gonthier MP, Remesy C, Scalbert A, Cheynier V, Souquet JM, Poutanen K and Aura AM. 2006. Microbial metabolism of caffeic acid and its sters chlorogenic and caftaric acid by human faecal microbiota in vitro. Biomed Pharmacother 60 536-540. 

Rechner, A.R., Spencer, J.P., Kuhnle, G., Hahn, U., and Rice-Evans, C.A., Novel biomarkers of the metabolism of caffeic acid derivatives in vivo, Free Radical Biol Med., 30, 1213, 2001. 

Lafay S, Morand C, Manach C, Besson C, Scalbert A. 2006b. Absorption and metabolism of caffeic acid and chlorogenic acid in the small intestine of rats. Br J Nutr 96 39 46. 

Moridani MY, Scobie H, O Brien PJ. 2002. Metabolism of caffeic acid by isolated rat hepatocytes and subcellular fractions. Toxicol Lett 133 141-151. 

Rechner AR, Spencer JPE, Kuhnle G, Hahn U, Rice-Evans CA. Novel biomarkers of the bioavailability and metabolism of caffeic acid derivatives in humans. Free Radic Biol Med 2001 30 1213-1222. 

Caffeic acid is metabolized by liver enzymes to give ferulic, vanillic acids and their glycine conjugates, which may be excreted into urine. In addition, dihydroferulic acid is produced by catechol o-methyltransferase in the liver. Because of the specificity of this enzyme, only ortho hydroxy-methoxy metabolites may be formed. These reactions may occur in rats as well in humans [15]. Fig. (2) shows the metabolic reactions of caffeic acid in body tissues. 

Fig. (2) Metabolic reactions of caffeic acid in body tissues...

A pure culture of the organism was inoculated into a basal medium with the addition of 0.025% caffeic acid. After 7 days incubation at 25°C under conditions of reduced oxygen tension, the caffeic acid was completely metabolized. Metabolites of caffeic acid are identified as dihydrocaffeic acid and ethyl catechol, respectively. In the 1960s, it has been reported that a constitutive enzyme present in strains of Aerobacter decarboxylates caffeic acid to 4-vinylcatechol nonoxidatively [20], Several cinnamic acids have been tested and the decarboxylation product from /7-coumaric acid has been identified as 4-vinylphenol. Thus, the bacterial enzyme activity requires a relatively unhindered 4-hydroxy group on the aromatic ring and an acrylic acid side chain. 

The metabohtes and eonjugates of caffeic acid and caffeic derivatives identified in the different studies in humans and animals are summarized in Table 1. The majority of studies in hmnans and animals on absorption and metabolism of hydroxyeinnamates have been imdertaken with caffeic acid and its main natural conjugate, chlorogenie acid. The possession of a catechol moiety results in extensive metabohsm of caffeic acid, which leads to the formation of a number of metabohtes. The metabolic pathways of caffeic acid are schematically summarized in Figure 1 [6,16]. 

Figure 1 The metabolic pathways of caffeic acid. (From Refs. 6,16.)...

In a study investigating the absorption of caffeic acid and chlorogenic acid in rats after oral administration, no absorption of chlorogenic acid and no metabolism in the small intestine were observed [23]. In contrast, caffeic acid was absorbed and detected in plasma post enzyme treatment accompanied by ferulic acid as a metabolite. Chlorogenic acid was only detected in urine of rats after intravenous administration (50 mg/kg) but also not after oral administration that finding is consistent with the hypothesis that major hydrolysis to release free caffeic acid occurs in the colon [24]. In an in vitro model using isolated rat small intestine, chlorogenic acid was also not absorbed, but caffeic... 

The action of catechol O-methyl transferase might be a central metabolic event after the absorption of free caffeic acid or some of its metabolites with a still intact catechol moiety, such as dihydrocaffeic acid or protocatechuic acid. In most studies administering chlorogenic acid or preparations rich in caffeic acid derivatives (i.e., coffee), only 0-methylated metabolites but no metabolites with an intact catechol group were detected in urine, supporting the central role of 0-methylation of caffeic acid post absorption [6,17,18]. Studying the O-methylation of caffeic acid in vitro by using rat or rabbit liver slices or preparations of liver, both possible O-methylation products, ferulic and iso-femlic acids, were formed, and a meta/para ratio of 2.8 1 was recorded [13]. In addition, the ability to reduce the residual double bond was also observed in vitro with rat or rabbit liver slices [10]. 

This cytotoxicity of calfeic acid, based on its catechol moiety and the interaction with cytochrome P450, might be the reason for the extensive O-methylation and glucuronidation of caffeic acid in humans observed in most studies investigating the absorption, metabolism, and ehmination of dietary calfeic acid derivatives. 

The feeding data in favour of this scheme are very convincing. When labelled precursors were fed to Daphne inflorescences, and allowed 20 hours for metabolism, the incorporation of p-coumaric acid into (12) was 27.8%, of cinnamic acid 12.8 %, and of caffeic acid only 0.80%. A similar experiment with a 4-day metabolic period gave the results p-coumaric acid 4S %, cinnamic acid 13 %, and caffeic acid 2.5 %. Experiments with Cichorium intybus gave a similar pattern of incorporation into (11). Equal amounts of the three precursor acids were fed and there was similar uptake, but the dilution value for p-coumaric acid was as low as 0.0224, whereas for cinnamic and caffeic acids the values were 1.36 and 1.10, respectively. 

For some toxins it is possible to demonstrate an apparent improvement in functional response at levels of exposure which are below a threshold. This effect, which has been termed hormesis , is most effectively demonstrated in the consistently improved longevity of animals whose caloric intake is restricted rather than allowing them to feed ad lib (Tannenbaum, 1942). Clearly in this instance, the observed effects are the result of exposure to a complex mixture of chemicals whose metabolism determines the total amount of energy available to the organism. But it is also possible to show similar effects when single chemicals such as alcohol (Maclure, 1993), or caffeic acid (Lutz et al., 1997) are administered, as well as for more toxic chemicals such as arsenic (Pisciotto and Graziano, 1980) or even tetrachloro-p-dibenzodioxin (TCDD) ( Huff et al., 1994) when administered at very low doses. It is possible that there are toxins that effect a modest, reversible disruption in homeostasis which results in an over-compensation, and that this is the mechanism of the beneficial effect observed. These effects would not be observed in the animal bioassays since to show them it would be necessary to have at least three dose groups below the NOAEL. In addition, the strain of animal used would have to have a very low incidence of disease to show any effect. 

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