The present studies demonstrate that polyphenols from RW and DRW are bioavailable and accumulate in plasma after regular consumption. Even though total antioxidant capacity in plasma did not change after RW or DRW consumption, both drinks affected DNA strand breaks in peripheral leukocytes. Results are contradictory, as DNA damaging effects of RW and DRW occur after single ingestion, whereas regular RW consumption seems to protect from endogenous DNA strand breaks. Further investigations are required to clarify whether interactions of red wine polyphenols with cellular DNA result in genotoxic or anticarcinogenic effects.
The results of the single-dose analysis confirm that polyphenols are bioavailable from both RW and DRW [8, 10, 11], and that alcohol does not significantly affect polyphenol absorption in humans [38–40]. Accumulation of phenolic compounds in plasma could be measured after regular consumption of RW corresponding to previous findings [16, 19] but not in group DRW. We assume that this is rather due to the slightly lower intake of polyphenols from DRW than to different alcohol content [38–40].
The impact of phenolic compounds from RW and DRW on the pro-/antioxidant balance in plasma seems to be low, as plasma antioxidant capacity was neither altered significantly in the short nor in the long term as also reported by others [7, 20, 22, 23]. There was no effect of RW or DRW consumption on antioxidant vitamins in the dietary intervention trial corresponding to the findings of previous studies [17, 20]. Interestingly, the concentration of vitamin C in plasma increased 360 min after consumption of one single dose of DRW whereas it decreased after RW suggesting that the polyphenols might act as antioxidants in vivo but this is counteracted by prooxidant effects of alcohol in native RW [13, 23]. Changes in vitamin C levels did not have a significant impact on plasma antioxidant capacity but might have protected cellular DNA from oxidation ex vivo, which will be discussed later on.
Uric acid, one of the main antioxidants contributing to plasma antioxidant capacity [13, 32], increased after single RW consumption as expected [13, 41]. However, the increase of 15% in TEAC observed after 90 min, even in combination with a 17% increase of total phenolic content did not lead to a significant rise of plasma TEAC. This supports the observations of Cao et al.  implying that the TEAC method is not sensitive enough to measure small changes in the pro-antioxidant balance after ingestion of foods rich in polyphenols.
Further changes of albumin, uric acid and bilirubin concentrations occurred in both trials, probably due to normal biological variance, but they were not associated with changes of plasma TEAC.
In contrast to antioxidant capacity, there was a significant effect of RW and DRW on DNA strand breaks in peripheral leukocytes suggesting interactions of red wine polyphenols with cellular DNA. Regular consumption of RW protects cellular DNA from strand breaks in vivo, which corresponds to findings of previous studies [18, 42], probably due to DNA stabilizing and/or antioxidant effects of RW polyphenols . In contrast, single ingestion of RW or DRW increased endogenous DNA strand breaks. This was not expected as DNA damaging effects of RW polyphenols have been observed only in vitro and for concentrations of 25–1000 μM [44–46], whereas in human plasma polyphenols occur mainly as metabolites and in concentrations below 1 μM . As the same outcome was found in groups RW and DRW, genotoxic effects of alcohol  can also be excluded. Since strand breaks occur during DNA repair via base or nucleotide excision , increased DNA strand breaks as observed in our study might also result from activation of DNA repair enzymes by polyphenols . To clarify the mechanisms, a modified protocol for the single cell gel electrophoresis allowing to separately assessing oxidation of purine and pyrimidin bases  as well as DNA repair kinetics  should be used in future studies.
The discrepancy between increased DNA strand breaks after single and reduced DNA strand breaks after repeated consumption of RW might be due to different polyphenols which might have been present in plasma or leukocytes after single or regular consumption, respectively. This would be plausible regarding the different elimination half lives of the various RW polyphenols and their metabolites [6, 39, 50, 51], but quantitative analysis of single polyphenolic compounds in plasma/cells would be necessary to confirm this. Furthermore, the different mode of RW consumption in the short- and the long-term study (after an overnight fast vs. regularly after dinner) could also provide an explanation. Since consumption of RW with meals reduces prooxidative effects occurring post-prandially [24, 52, 53], the DNA protective effects of RW in our dietary intervention trial might have resulted from reduced prooxidative effects of the meals, which were lacking in the single-dose analysis.
Exogenous DNA strand breaks, which reflect the activity of non-enzymatic antioxidants [35, 37], have only been reduced after single consumption of DRW, which corresponds to the results of a recent study showing that consumption of 300 mL DRW protected lymphocytes from radiation-induced DNA damage ex vivo . As in our study the plasma phenolic content was not different between groups RW and DRW, the increased vitaminC concentration in plasma observed in group DRW might have protected leukocyte DNA against oxidative stress ex vivo. Indeed, DNA protecting effects of vitamin C have been described in vitro [54, 55] and are also supposed to occur in vivo [36, 56, 57]. This is also supported by Greenrod et al.  who observed that the contribution of catechin to DNA protecting effects or DRW is quite small, and that other factors seem to play an important role.
It has to be noted that in the dietary intervention trial consumption of RW and DRW lead to an increase in flavonoid intake compared to baseline and to controls, whereas phenolic acid consumption increased in RW, DRW and controls after 6 weeks compared to baseline without any differences between the groups. This is probably due to seasonal variations of the food pattern as our study period was between May and July, when consumption of fresh fruit rich in phenolic acids increased (data not shown). Hence, the observed effects of RW on DNA strand breaks in peripheral leukocytes can be attributed to the additional intake of flavonoids rather than to phenolic acids.
The major advantage of our study compared to others is the investigation of both single and regular consumption of RW and DRW which has only been done so far by Cartron et al. . In both studies substantial differences between short- and long-term effects occurred implying that single-dose analysis alone are not appropriate to investigate potential health effects of red wine consumption.
However, our study has some constraints, regarding the different polyphenol intake with RW and DRW, which does not allow a direct comparison of both study drinks. In future studies, drinks with equal polyphenol composition should be applied. Moreover, in the single dose analysis TPP increased 360 min after intervention in groups RW and DRW, but also in controls. This could be due to 1) unknown amounts of polyphenols in "permitted" foods (e.g. white bread or pasta). These foods are generally considered to be low in polyphenols and thus, are not listed in the polyphenol database [27, 28]. Nevertheless, they may have provided considerable amounts of polyphenols, especially phenolic acids  leading to an increase of TPP in the control group. 2) As food intake at lunchtime was not recorded, we cannot exclude that the volunteers failed to comply with the polyphenol poor diet in the time interval between blood sampling at 90 and 360 min. To avoid these confounding factors in future short-term studies we strongly recommend to provide the subjects with standardized amounts of polyphenol free formula diets instead of foods low in polyphenols ad libitum.
It is unlikely that random inhomogeneities of the groups (Table 1) would have influenced our results. In the single-dose analysis, control subjects were only slightly older (≈ 5 years) than those in group RW and DRW and therefore metabolic alterations are not expected. In the dietary intervention trial, the higher body weight and BMI in group RW could have reduced the response to RW, as the intake of polyphenols / kg body weight was lower in that group. However, effects on plasma phenolic content and DNA strand breaks occurred only with RW, and even more pronounced effects might have been observed in subjects with a lower body weight.