Oxidative Metabolites of Lycopene and Their Biological Functions - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 418

insulin-like growth factor binding protein (IGFBP), and the inhibition of cell proliferation and the
induction of apoptosis. With the cloning and the characterization of two distinct carotenoid cleaving
enzymes, recent research has focused on the metabolic fate of lycopene and the subsequent metabo-
lites created. Several reports, including our own, suggest that the biological activities of lycopene
may be mediated, in part, by lycopene metabolites. Lycopene metabolites, and carotenoid metabo-
lites in general, can possess either more or less activity than the parent compound or can have an
entirely independent function. The chemical and biological metabolisms of lycopene and the poten-
tial actions of lycopene and its metabolites on chemoprevention will be highlighted in this chapter.

20.2 FORMATION OF LYCOPENE METABOLITES IN VITRO
Carotenoids are a class of lipophilic compounds with a polyisoprenoid structure. Most carote-
noids contain a series of conjugated double bonds, which are sensitive to oxidative modii cation
and cis-trans isomerization. There are six major carotenoids (b-carotene, a-carotene, lycopene,
b-cryptoxanthin, lutein, and zeaxanthin) that can be routinely found in human plasma and tis-
sues. Among them, b-carotene has been the most extensively studied. More recently, lycopene has
attracted considerable attention due to its association with a decreased risk of certain chronic dis-
eases, including cancers. Considerable efforts have been expended in order to identify its biological
and physiochemical properties. Relative to b-carotene, lycopene has the same molecular mass and
chemical formula, yet lycopene is an open-polyene chain lacking the b-ionone ring structure. While
the metabolism of b-carotene has been extensively studied, the metabolism of lycopene remains
poorly understood.

20.2.1 C HEMICAL O XIDATION OF L YCOPENE
There have been a number of reports studying the formation of lycopene metabolites and oxidation
products in vitro . Many of these studies have utilized various oxidizing systems and have iden-
tii ed several unique metabolites. Using three separate solubilization schemes (toluene, aqueous
Tween 40, and liposomal suspension), Kim and colleagues (2001) identii ed several oxidative prod-
ucts after the incubation of lycopene under atmospheric oxygen, including 3,7,11-trimethyl-2,4,6,
10-dodecatetraen-1-al; 6,10,14-trimethyl-3,5,7,9,13-pentadecapentaen-2-one; acyclo -retinal, apo-14 ′ ,

and 12 -lycopenal. It was subsequently demonstrated that acyclo -retinal could be

oxidized to the corresponding acyclo -retinoic acid (ACR) when incubated with pig liver homoge-
nate (Kim et al. 2001) indicating potential in vivo formation. The incubation of deuterated lycopene
with rat intestinal post-mitochondrial fractions and soy lipoxygenase led to the identii cation of
several additional lycopene metabolites and oxidative products, such as 3-keto-apo-13-lycopenone;
3,4-dehydro-5,6-dihydro-15,15

′ -, 10 ′ -, 8 ′ -, and 6 ′

′ -apo-lycopenal; 2-apo-5,8-lycopenal-furanoxide; lycopene-5,6,5 ′ ,6 ′ -

diepoxide; lycopene-5,8-furanoxide; and 3-keto-lycopene-5 -furanoxide (Ferreira et al. 2003).

Zhang et al. exposed lycopene to atmospheric oxygen and a perfusion of ozone and identii ed
( E , E , E )-4-methyl-8-oxo-2,4,6-nonatrienal as a lycopene oxidative product, which induced apoptosis
in HL-60 cells (Zhang et al. 2003). Using a combination of hydrogen peroxide and osmium tetroxide
(Aust et al. 2003), an oxidized lycopene mixture was separated and, using an increase in gap junc-
tion communication (GJC) as a marker for bioactivity, a new metabolite was tentatively identii ed as
2,7,11-trimethyl-tetradecahexaene-1,14-dial (Aust et al. 2003). Using a separate oxidizing method,
Caris-Veyrat et al. identii ed an extensive number of lycopene oxidative products (Caris-Veyrat
et al. 2003). The oxidation of lycopene by potassium permanganate produced eight apo-lycopenals,
three apo-lycopenones, and six apo-carotendials as detected by HPLC-DAD-MS. Taken together,
the results from these studies suggest that the susceptibility of carbonyl compounds to cleavage by
autooxidation, radical-mediated oxidation, and singlet oxygen occurs in carotenoids with a long-
chain of conjugated double bonds. Although the signii cance of such oxidative metabolites remains
poorly understood, these products may be produced in vivo (if the tissues are exposed to oxidative
stress, such as smoking and drinking) and have certain biological activities.

′ ,8 ′