Carotenoid Uptake and Protection in Cultured RPE - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 318

The importance of ABCR protein in retinal degeneration is underscored by epidemiologic data
showing that certain variants of ABCR gene are a causative factor for Stargardt's disease and are
associated with an increased susceptibility to AMD in a subpopulation of AMD patients (Allikmets,
2000; Allikmets et al., 1997; Bernstein et al., 2002a). ABCR is responsible for transport of all- trans -
retinal-phosphatidylethanolamine conjugate from the inner leal et of photoreceptor disc membrane
to the outer leal et enabling its enzymatic reduction to all- trans -retinol (Beharry et al., 2004)
(Figure 15.2c). In the absence of ABCR in knockout animals or in cases of ABCR dysfunction as
observed in Stargardt's disease patients with mutated ABCR , elevated amounts of all- trans -retinal
accumulate in POS upon exposure to light and photobleaching of visual pigments (Mata et al., 2000,
2001; Weng et al., 1999). As a result, early in life affected people and animals accumulate large
amounts of lipofuscin.
Therefore, it may be speculated that elevating levels of vitamin A through supplementation
in the retina with fully functional synthesis of 11- cis -retinal from all- trans retinol but dysfunc-
tional transport of retinoids, such as in the aged retina or retina with dysfunctional ABCR, may
increase the risk of retinal-mediated damage. At present, several drugs are being tested or developed
with the aim to decrease the efi ciency of the retinoid cycle (Golczak et al., 2005a, b; Maiti et al.,
2006; Radu et al., 2003, 2005; Travis et al., 2007).

15.3.2.3 Expression and Secretion of Lipoproteins by the RPE
Once internalized within the RPE, there must be a mechanism for carotenoid transport to photore-
ceptors. The RPE metabolizes lipids from phagocytosed POS and provides a constant supply of lip-
ids to photoreceptors for the synthesis of new discs and molecular renewal of lipids within existing
discs (Strauss, 2005). Thus there is a constant transfer of lipids from the RPE to photoreceptors. It
has been shown in the rabbit and monkey that intraveneous administration of lipophilic benzopor-
phyrin bound to LDLs results in an efi cient delivery of the l uorescent photosensitizer not only to
the RPE but also to photoreceptors; this occurs within 20 min following injection (Haimovici et al.,
1997; Miller et al., 1995).
These data suggest that one of possible mechanisms of carotenoid delivery to the neural retina
may involve lipoprotein uptake from the basal side of the RPE followed by its retro-endocytosis on
the apical site (Lorenzi et al., 2008). Alternatively, the endocytosed lipoprotein may be degraded
in the RPE followed by secretion of certain lipophilic components from the lipoprotein at the api-
cal site. Due to low solubility of carotenoids in aqueous solutions, it may be suggested that they are
secreted already bound to a protein or that an acceptor protein is available in the interphotoreceptor
matrix and/or POS.
In the neural retina there are at least two types of proteins with high afi nity and specii city
for binding of lutein and zeaxanthin (Bhosale and Bernstein, 2007; Bhosale et al., 2004; Loane et
al., 2008; Yemelyanov et al., 2001). Bernstein and colleagues have isolated two xanthophyll bind-
ing proteins (XBPs) from human retina having molecular weights of 25 and 55 kDa (Yemelyanov
et al., 2001). They have shown that these XBPs have high afi nity for lutein, 3 -epilutein, meso-

zeaxanthin, b-cryptoxanthin, and zeaxanthin, substantially smaller for a diketodihydroxycarotenoid,
astaxanthin, while binding of b-carotene or the diketocarotenoid, canthaxanthin, was negligible
(Yemelyanov et al., 2001). In their subsequent study of XBPs, Bernstein et al. have purii ed from
human retina a protein fraction corresponding to 23 kDa which then has been resolved into four
components using two-dimensional gel electrophoresis (Bhosale et al., 2004). The most prominent
component has been identii ed as glutathione-S-transferase class pi (GSTP1) and has been shown to
bind zeaxanthin and meso-zeaxanthin with high afi nity, but not lutein (Bhosale et al., 2004).
GSTP1 belongs to a superfamily of phase II detoxii cation enzymes, glutathione transferases
(GSTs), which become upregulated in response to oxidative stress. Mammalian GSTs are divided
into three major families: cytosolic, mitochondrial, and microsomal GSTs (Hayes et al., 2005).
Cytosolic and mitochondrial GSTs are soluble enzymes, whereas microsomal GSTs are membrane

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