Absorption and metabolism of red wine polyphenols and their potential health benefits in cardiovascular function

In a recent issue of the Journal, Chiva-Blanch et al (1) reported the differential effects of the polyphenols and alcohol in red wine (RW) on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis in subjects at high risk of cardiovascular disease. We appreciate the authors’ cautious deduction that both ethanol and nonalcoholic compounds contribute to the antiinflammatory effects of RW on the basis of a randomized clinical trial of RW and dealcoholized RW (DRW). Although we have little doubt about the alcohol-independent cardiovascular effects of the phenolic compounds of RW, we were concerned about the actual concentrations of urinary polyphenols and their metabolites reported in the study. The authors reported that 24-h urinary excretion of total resveratrol metabolites increased in relation to baseline amounts from 1.24 lmol (95% CI: 0.91, 1.65 lmol) to 4.69 lmol (95% CI: 3.86, 5.53 lmol) and 8.33 lmol (95% CI: 6.86, 10.19 lmol) after ingestion of RW and DRW, respectively. The authors suggested that resveratrol metabolite concentrations were statistically higher after the DRW compared with RW intervention (P 1⁄4 0.002). However, it seems clear from a great number of recent studies that the cardiovascular effects of polyphenols are dependent on their bioavailability, and alcohol in RW may improve polyphenol availability by increasing its intestinal absorption or by delaying its excretion (2, 3), indicating that RW intake should produce higher concentrations of urinary resveratrol metabolites than DRW ingestion. It is, therefore, reasonable to assume that the consumption of RW and DRW also should, at least, lead to similar concentrations of urinary resveratrol metabolites, despite the fact that the resveratrol content of RW is slightly higher than that of DRW as depicted in Table 1 of their article. More important, we also recognized that the observed significant increase (P 1⁄4 0.002) in urinary resveratrol metabolites after DRW intake was not paralleled by the increase in the tested biomarkers related to atherosclerosis in comparison with RW ingestion (Tables 4 and 5 of their article). Therefore, the present data make sense if RW polyphenols, including resveratrol, are associated with the tested vascular health benefits. One of the main limitations of Chiva-Blanch et al’s study (1) is that it does not report the circulating metabolite concentrations after the consumption of RW and DRW. To elucidate the finding that polyphenols are responsible for the alcoholindependent cardiovascular effect of RW, plasma analysis for polyphenols and their metabolites is determinant. Several causality criteria for the assessment of any compound as a potential mediator of vascular function have been established previously, and these have to meet the condition that the test compound should be absorbed from a food matrix by humans and should be transported to the appropriate site or tissue (as quantifiable in circulation), and its circulating amounts temporally parallel the hypothesized vascular effects (4, 5). Although the study conducted by Chiva-Blanch et al (1) showed consistent effects of both RW and DRW on several intermediate markers for vascular function, it is still not fully known whether their action could be specifically related to RW polyphenols. Another limitation of this study was that although the authors measured total urinary resveratrol metabolites as an indicator of polyphenolic absorption, 24-h urinary excretion results of total resveratrol metabolites were not corrected for creatinine (eg, nmol/g creatinine). It also must be noted that the authors omitted a necessary explanation as to whether the analysis of total resveratrol metabolites was to measure total resveratrol concentrations, which are calculated as the sum of resveratrol and its sulfated or glucuronidated metabolites after enzymatic hydrolysis with glucuronidase and sulfatase, as well as methylated resveratrol. It is well known that, in humans, ingested polyphenols are extensively metabolized and excreted as sulfated, glucuronidated, or methylated phase II conjugates (5–7), and authentic standards of resveratrol metabolites are not generally commercially available. It is also surprising that the study design was to elucidate whether the cardioprotective effects of RW intake are attributed to alcohol, polyphenols, or the synergistic effect of both, although the concentration-dependent effects of resveratrol metabolites and ethylglucuronide as the indicators of polyphenolic and alcohol absorption from RW, DRW, and gin were not adequately discussed in the article. The observed results did not well support the hypothesis raised by authors that the ethanol and polyphenols in RW were responsible for the regulation of soluble inflammatory mediators in high-risk patients. Epidemiologic studies have shown that moderate intake of RW protects against cardiovascular diseases, and this effect has been attributed to polyphenols (2, 3, 8, 9). However, Chiva-Blanch et al (1) noted that there was inadequate experimental evidence to implicate specific polyphenols in RW. Data on the intestinal absorption of polyphenols from RW intake are sparse, and it is not yet known to what extent these components are bioavailable and whether alcohol plays a role in their absorption. Dietary intake of polyphenols is not guaranteed to equate with exposure at the tissue level, because polyphenols from food, including RW, are poorly absorbed in humans (8). Given this, the possibility that RW polyphenols affect vascular function is intriguing and deserves attention in future studies.