Carotenoids as Modulators of Molecular Pathways Involved in Cell Proliferation and Apoptosis - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 470

through antioxidant response element (ARE) found in the regulatory regions of their genes. The
transcription factors NrF2, which bind to ARE, seem to be essential for the induction of phase II
enzymes, such as glutathione S-transferases, NAD(P)H quinone oxidoreductase (NQO1), as well as
heme oxygenase-1 (HO-1) and the thiol containing reducing factor thioredoxin. Carotenoids have
been shown to modulate tumor growth acting as potent inducers of these enzymes (Ben-Dor et al.,
2005). b-Carotene has been found to modulate the expression of HO-1, decreasing it, as observed
in cultured FEK4 cells (Trekli et al., 2003) or i broblasts (Offord et al., 2002) exposed to UVA or
increasing it, as observed in human skin i broblasts enriched with the carotenoid and exposed to
UV-light (Obermuller-Jevic et al., 2001). In this study, the prooxidant effects of b-carotene were
totally suppressed by vitamin E, but only moderately by vitamin C (Obermuller-Jevic et al., 2001).
The modulation of this enzyme may occur through an activation of MAPK leading to induction of
ARE, as suggested for other dietary chemopreventive compounds (Owuor et al., 2002). An alterna-
tive mechanism to explain the regulation of HO-1 expression by b-carotene has been recently sug-
gested (Palozza et al., 2005b). In this study, the carotenoid controlled HO-1 expression through the
induction of Bach1, known to act as a HO-1 repressor gene, in i broblasts exposed to cigarette smoke
condensate (Palozza et al., 2006b).
Several lines of evidence suggest that lycopene also acts as an inducer of the activity and/or of
the expression of phase II enzymes in healthy animals (Breinholt et al., 2000) as well as in animals
bearing tumors, including gastric (Velmurugan et al., 2002) and DMBA-induced hamster buccal
pouch (Bhuvaneswari et al., 2002) tumors. At the same time, enzymes of oxidative defense were
induced and lipid peroxidation was reduced (Bhuvaneswari et al., 2002, Velmurugan et al., 2002)
by the carotenoid.
It has been recently reported that in transiently transfected cancer cells lycopene transactivated
the expression of reporter genes fused with ARE sequences. Other carotenoids such as phytoene,
phytol uene, b-carotene, and astaxanthin had a much smaller effect. An increase in protein as well
as mRNA levels of the phase II enzymes NQO1 and g-glutamylcysteine synthetase was observed in
nontransfected cells after carotenoid treatment. The potency of the carotenoids in ARE activation
did not correlate with their effect on intracellular reactive oxygen species and reduced glutathione
level, which may indicate that ARE activation is not solely related to their antioxidant activity. The
increase in phase II enzymes was abolished by a dominant-negative Nrf2, suggesting that carote-
noid induction of these proteins depends on a functional Nrf2 and the ARE transcription system
(Ben-Dor et al., 2005).

22.7 MODULATION OF XENOBIOTIC AND OTHER ORPHAN
NUCLEAR RECEPTORS
Orphan receptors are structurally related to nuclear hormone receptors but lack known physiologi-
cal ligands. Xenobiotic receptors represent a family of orphan receptors and make up part of the
defense mechanism against foreign lipophilic chemicals (xenobiotics). They include the steroid
and xenobiotic receptor/pregnane X receptor (PXR), constitutive androstane receptor, and the aryl
hydrocarbon receptor. These receptors respond to a wide variety of drugs, environmental pollutants,
carcinogens, dietary and endogenous compounds and regulate the expression of cytochrome P450
(CYP) enzymes, conjugating enzymes and transporters involved in the metabolism and elimination
of xenobiotics. It has been reported that carotenoids may modulate the expression of detoxii cation
enzymes (Paolini et al., 1999, 2001; Perocco et al., 1999). Recently, it has been shown that b-car-
otene can act as an inducer of several carcinogen-metabolising enzymes in the lung of Sprague-
Dawley rats (Paolini et al., 2001). They include CYP1A1/2, CYP3A, CYP2B1, and CYP2A. Such
inductions have been associated to an overgeneration of reactive oxygen centered radicals (Paolini
et al., 2001). In addition, many tobacco smoke pro-carcinogens are themselves CYP inducers and
could act in a synergistic way with b-carotene or with some of its oxidation products, such as b-apo-
8

′ -carotenal, further contributing to the overall carcinogenic risk (Wang et al., 1999). Moreover,