Oxidative Metabolites of Lycopene and Their Biological Functions - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 424

20.4.2 G AP J UNCTION C OMMUNICATION
Gap junctions are cell-to-cell channels that enable connected cells to exchange nutrients, waste
products, and information. Each gap junction is derived from six connexin proteins from each
adjacent cell for a total of 12 connexin proteins. The connexin family has >20 connexins that are
expressed in mammals with both cell and developmental specii cities of expression (Bertram 2004).
Although there are >20 connexins, connexin 43 (Cx43) is the most widely expressed connexin.
More interestingly, Cx43 is the connexin most often induced by retinoids and carotenoids. GJC has
been implicated in the control of cell growth via adaptive responses: differentiation, proliferation,
and apoptosis (Trosko et al. 1998). A large body of evidence now indicates the loss of gap junctional
communication as a hallmark of carcinogenesis (King and Bertram 2005).
Targeting connexins as a possible strategy for chemoprevention has been suggested (King and
Bertram 2005). Retinoids and carotenoids increase GJC between normal and transformed cells
(Hossain et al. 1989, Zhang et al. 1991). It was demonstrated that both provitamin A and non-provi-
tamin A carotenoids inhibited carcinogen-induced neoplastic transformation (Bertram et al. 1991)
and upregulated Cx43 mRNA expression (Hossain et al. 1989, Zhang et al. 1991). Furthermore,
whereas treatment with retinoic acid increased Cx43 expression within 6 h, carotenoid treatment
required approximately three times longer and produced the same response (Rogers et al. 1990,
Zhang et al. 1992). This lag in activity is often attributed to the formation of active metabolites.
Several lines of in vitro evidence indicate that carotenoid oxidative products/metabolites may
be responsible for increased GJC, especially in the case of lycopene. After the complete oxidation
of lycopene with hydrogen peroxide and osmium tetroxide, Aust et al. (2003) isolated an oxidative
metabolite that effectively increased gap junction communication. The compound, identii ed as
2,7,11-trimethyl-tetradecahexaene-1,14-dial, induced GJC to a level comparable to retinoic acid.
The oxidative metabolite lycopene-5,6-epoxide, which is found in tomatoes (Khachik et al. 1995)
was shown to increase Cx43 expression in human keratinocytes (Khachik et al. 1995). Stahl et al.
demonstrated that the central cleavage product of lycopene, ACR, could increase GJC (Stahl et al.
2000). However, an effect of ACR on GJC was only achieved at high concentrations indicating that
the contribution of ACR to the activity of lycopene on GJC appears to be minimal. More recently,
we have demonstrated the cleavage of lycopene to apo-10 -lycopenal by ferret CMO2 (Hu et al.

2006). While the Cx43 promoter does not contain an retinoic acid response element (RARE), it
has been reported that retonic acid receptor (RAR) antagonists inhibited upregulation by retinoids
and had no effect on the effect of carotenoids (Hix et al. 2005). This is interesting due to the effect
of both oxidative metabolites and enzymatic cleavage metabolites of lycopene on modulating GJC,
which could provide two separate pathways of increasing GJC. Considering the bioconversion of
lycopene into apo-10

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-lycopenoids, whether apo-10-lycopenoids contribute to lycopene activity on
GJC warrants further study.

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20.4.3 R ETINOID A CTIVITY
b-Carotene and its excentric cleavage metabolites can serve as direct precursors for all- trans -
retinoic acid and 9- cis -retinoic acid (Napoli and Race 1988, Wang et al. 1994, 1996), which are
ligands for both RARs and RXRs. Retinoid receptors function as ligand-dependent transcription
factors and regulate gene expression by binding as dimeric complexes to the RARE and the retinoid
X response element, which are located in the 5 promoter region of responsive genes. RXR can not

only form dimeric complexes with RAR but can also dimerize with other members of the nuclear
hormone receptor superfamily, such as thyroid hormone receptors, the vitamin D receptors, PPARs,
and possibly other receptors with unknown ligands designated or orphan receptors.
Upregulation of retinoid receptor expression and function by provitamin A carotenoids may play a
role in mediating the growth inhibitory effects of retinoids in cancer cells (Lian et al. 2006, Prakash
et al. 2004). However, it is unclear if non-provitamin A carotenoids and their metabolites may act

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