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The ratio of cis and all-trans lycopene (LYC) in human and animal tissues exceeds that in foods. The basis for this difference remains unknown, although differences in their stability, transport, and metabolism have been suggested. Here, we systematically compared the digestive stability, efficiency of micellarization, and uptake and intracellular stability of cis and all-trans isomers of LYC and carotenes using the coupled in vitro digestion and Caco-2 human intestinal cell model. Aril and oil from the carotenoid-rich gac fruit (Momordica cochinchinensis Spreng) were cooked with rice to provide a natural source of LYC and carotenes. The ratio of cis:trans isomers of LYC and β-carotene was similar before and after simulated gastric and small intestinal digestion with recovery of total carotenoids in the digesta exceeding 70%. Micellarization of cis isomers of LYC during digestion of meals with both gac aril and oil was significantly greater than that of the all-trans isomer but less than for the carotenes. Uptake of cis isomers of LYC by Caco-2 cells was similar to that of carotenes and significantly greater than all-trans LYC. Micellarized carotenoids were relatively stable in micelles incubated in the cell culture environment and after accumulation in Caco-2 cells. These data suggest that the greater bioaccessibility of cis compared with all-trans isomers of LYC contributes to the enrichment of the cis isomers in tissues and that gac fruit is an excellent source of bioaccessible LYC and provitamin A carotenoids.

Discussion

The absorption of carotenoids, like other highly lipophilic compounds in the diet, requires the partitioning of these compounds in bile salt micelles during small intestinal digestion, uptake across the brush border membrane of enterocytes, and incorporation into chylomicron particles for secretion into lymph. The transfer of carotenoids from the food matrix to micelles is referred to as bioaccessibility and represents the potential for their absorption or bioavailability. The primary finding of this study is that both the transfer of cis isomers of LYC to micelles during the digestion of rice meal with gac aril or oil and the subsequent uptake of cis LYC by Caco-2 intestinal epithelial cells were more efficient than that of all-trans LYC. These results suggest that such differences in the gastrointestinal processing of ingested cis and all-trans isomers of LYC contribute to the markedly increased ratio of cis:all-trans isomers in tissues compared with fresh and processed foods.

The ratio of cis:all-trans LYC remained relatively constant during simulated digestion of the test meal. Limited conversion of all-trans to cis isomers of LYC was reported when tomato paste was added to simulated and human gastric fluids (9) and within the stomach of ferret and human subjects (8,11). Boileau et al. (8) also observed more efficient incorporation of cis LYC into synthetic bile salt micelles, as well as greater enrichment of cis isomers compared with all-trans LYC in intestinal mucosa of ferrets. Our observation that the ratio of cisvall-trans LYC was stable within micelles generated during simulated digestion and following uptake by Caco-2 cells suggests that the observed enrichment of cis isomers is due to their more efficient uptake and not isomerization of all-trans:cis isomers in these compartments. It has been postulated the bends in the cis configurations decrease space occupied by the molecule in comparison to the linear all-trans structure. This likely prevents aggregation and crystal formation in lipid droplets, thereby facilitating incorporation into mixed micelles (24,25). It also is possible that the cis configuration of LYC may bind more favorably to membrane transporters responsible for the uptake of carotenoids across the brush border membrane of absorptive intestinal cells (26,27).

Increased bioaccessibility of cis LYC suggests greater bioavailability compared with all-trans LYC. Isomer-dependent differences in incorporation of LYC isomers in chylomicrons were not investigated in this study. However, Stahl and Sies (28) reported that cooking tomatoes increased the content of cis isomers of LYC and the absorption of LYC in human subjects. Recently, Unlu et al. (29) reported that fractional absorption of LYC from tangerine tomato sauce containing 97% tetra-cis and other cis isomers was 2.5 times greater than LYC from a high βC variety of tomato that contained all-trans LYC as the predominant isomer. The most abundant isomer of LYC in the triglyceride-rich fractions from the human subjects was the same as ingested, suggesting minimal isomerization during digestion and absorption. Burri et al. (30) also conducted a crossover human study feeding sauces made from tangerine or red tomatoes. They found that serum all-trans LYC concentrations increased more in the presence or after feeding the sauce containing tetra-cis and also containing all-trans LYC and other cis LYC isomers. Their data suggest that cis isomers of LYC might facilitate the absorption of all-trans LYC. Similar to the reported results with cis and all-trans isomers of LYC in the rice meals with gac, we also have observed that the incorporation of tetra-cis and other cis isomers of LYC into micelles during simulated digestion of fresh and cooked tangerine tomatoes significantly exceeds that of all-trans LYC in digested Roma tomatoes (M. Failla, M. Pusateri, C. Chitchumroonchokchai, and S. Schwartz, unpublished data).