**3. Changes in the physicochemical properties of carotenoids by**  *Z***-isomerization**

Changes in the bioavailability and functionality of carotenoids after *Z*-isomerization should have strong correlations with changes in their physicochemical properties. Several reports have shown that the *Z*-isomerization of carotenoids can induce changes in various properties such as the stability, solubility, and crystallinity. Some computational approaches using a Gaussian program have revealed that the *Z*-isomerization of carotenoids affected the Gibbs free energy [34, 35, 108, 109], that is, the relative stability of all-*E*- and mono-*Z*-isomers were in the following order: all-*E*-isomer ≈ 5*Z*-isomer > 9*Z*-isomer > 13*Z*-isomer > 15*Z*-isomer > 7*Z*-isomer ≈ 11*Z*-isomer for lycopene [34, 35, 108]; all-*E*-isomer > 9*Z*-isomer > 13*Z*-isomer > 15*Z*-isomer > 7*Z*-isomer ≈ 11*Z*-isome for β-carotene [109]. Thus, (all-*E*)-carotenoids should be more stable than the *Z*-isomers, which was confirmed experimentally by Murakami et al. [36] using lycopene isomers. Changes in the Gibbs free energy, stability, of carotenoids following *Z*-isomerization would affect their antioxidant activities. In addition, there is limited experimental evidence that the *Z*-isomers of carotenoids such as lycopene, β-carotene, and astaxanthin have higher solubility in vegetable oil, organic solvents and SC-CO2 than the all-*E*-isomer [28–32, 110, 111], for example, the solubility of lycopene *Z*-isomers in ethanol was over 4000 times higher than that of the all-*E*-isomer [29]. These properties should affect the bioavailability of carotenoids. Namely, *Z*-isomerization of carotenoids could enhance uptake into bile acid micelles due to an increased solubility; thus, the bioavailability of lycopene and astaxanthin was improved [20–22]. On the other hand, regarding β-carotene and lutein, whose *Z*-isomers showed lower bioavailability [15, 41–48, 105], the uptake into bile acid micelles could potentially be improved by *Z*-isomerization, but they might have lower transport efficiency in enterocytes due to the activities of several carotenoids transport proteins, which are temporarily present at the apical membrane [27, 49–51]. *In vitro* tests of lutein support this hypothesis, that is, the *Z*-isomers showed higher bioaccessibility than the all-*E*-isomers in a digestion model [15, 105], whereas the opposite result was obtained in Caco-2 cells [15]. It has been predicted that *Z*-isomers of lycopene and astaxanthin can be efficiently internalized via carotenoid transporters, based on the results of testing conducted using Caco-2 cells [23, 76]. The abovementioned theory is strongly supported by the observations that, in human blood, over 50% of total lycopene exists in the *Z*-form, but only 5% of total β-carotene exists in the *Z*-form [112]. To attain a better understanding of the underlying mechanisms, further study on the uptake process of (*Z*)-carotenoids in enterocytes by carotenoid transport proteins is necessary. Furthermore, the crystallinity of carotenoids was changed by *Z*-isomerization: although (all-*E*)-carotenoids existed in a crystalline state, the *Z*-isomers were in an amorphous state, which was confirmed by optical observations, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy analyses [20, 28, 29, 113]. The change in crystallinity resulting from *Z*-isomerization may also influence changes in carotenoid bioavailability and functionality.

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