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Mechanisms and Biomarkers (WG 4) page 39
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promote an up-regulation of the GAP junctions. This mechanism may account for some of the
noted increase in GAP, but it is not the whole story.
When lycopene, present in serum or LDL is examined by HPLC, several isomers are present.
The majority of the lycopene in tomatoes is in the all-trans state, while that isolated from
plasma consists of both trans and cis-isomers. One suggested mechanism of lycopene activity
is its oxidation or cleavage to generate compounds of biological activity.
Khachik (1997) identified two oxidative metabolites of lycopene with 5 membered ring end
groups. These compounds were identified in both human milk and serum. The metabolites
were identified as a pair of 2,6-cyclolycopene-1,5-diols. At present it is not certain if these
components arose by in-vivo oxidation of lycopene or if they are of dietary origin. However
the biological activity of these compounds is unknown at this present time.
As previously stated β-Carotene has provitamin A activity, and this is synthesised by
enzymatic cleavage at the central double bond of carotene. This conversion occurs in the
intestinal cells. Another mechanism of that may yield retinoids is eccentric cleavage, at
random positions along β-carotene. The autoxidation of β-carotene results is eccentric
cleavage of the molecule producing retinal and β-apo-carotenals. This mechanism would
suggest that non-provitamin A carotenoids such as lycopene can be cleaved to retinoid like
fragments under oxidative conditions in the tissues. In vitro oxidation (Nagao 1999) of
lycopene produced γ-retinoic acid, γ-retinal and a series of apo-lycopenals was also identified.
Stahl (2000) went one stage further and proposed a biological function for a potential
metabolite of eccentric cleavage of lycopene called acyclo-retinoic acid. This study
investigated the effect of lycopene and its oxidative cleavage product on gap junction
communication in human fetal skin fibroblasts. Lycopene stimulated gap junction
communication, while a 10 fold concentration of the acyclolycopene was needed to produce a
similar effect. It was concluded that in the case of lycopene, its breakdown to the retinoic acid
analogue is of minor importance. Interestingly lycopene itself did not promote gene
expression in this study. This would imply that lycopene acts in an independent way to
retinoic acid. Could the carotenoid act at the membrane level to increase the level of
communication between the cells?
Phase I and phase II enzymes
The chemopreventative properties of carotenoids, particularly β-carotene was thought to be
linked with the synthesis of detoxification enzymes particularly cytochrome P450. Studies by