Drug Design and Development Gerardo Ulibarri

Tomato (Solanum lycopersicum)

Axel Gmez-Ortigoza 0317218

The common tomato (Solanum lycopersicum or Lycopersicon esculentum)
originated in Mexico and Peru. Even when it developed in this vast area, it was in
Mexico where it was first incorporated into the diet and used as food. The
Spaniards, who brought it from Tenochtitlan, popularized it by presenting it to
western civilization. Later it was familiarized in all the Spanish colonies including
the Philippines. It belongs to the nightshade family (Solanaceae), and its
botanically classified as a fruit. The plant typically grows from 1 to 3 meters. An
average common tomato weighs approximately 100 grams.

The fruit is rich in lycopene, a carotenoid also present in watermelons and papayas
as well as in algae. Lycopene is the most abundant carotenoid in tomatoes with
concentrations ranging from 0.94.2 mg/100 g depending upon the variety. Its
been widely known that this compound offers a variety of health benefits,
including: reducing cardiovascular disease risk, reducing osteoporosis, and
antioxidant activity; which can reduce the risk of cancer (i.e. prostate cancer). This
red phytochemical contains 40 carbon atoms and 56 hydrogen atoms; which adds
to a total molecular mass of 536 grams per mole. Structurally, it is a Tetraterpene
hydrocarbon assembled from eight isoprene units (Breemen et al., 2008).

Figure 1. Lycopene molecule.


Some of its properties include solubility in water,
and its red color. Lycopene has eleven conjugated
double bonds, which confer the red color and
antioxidant activity. Naturally, all of these bonds are
presented in the trans conformation constituting 72
possible stereoisomers. When exposed to light it
undergoes isomerization into the cis form, this
reaction is responsible for its antioxidant activity
(Rao et al., 2007). Additionally it is soluble in
organic solvents such as chloroform, benzene and
Figure 2. Trans to cis isomerization.
ether. It is easily destroyed by ROS (reactive oxygen species), what contributes to
its anti-oxidant activity.

Its biological roles range from
participating in photosynthesis (light
attraction through pigment-protein
complexes) to protecting against
excessive exposure to U.V. rays. By being
incorporated into specific biological
subcellular compartments it can
regulate such mentioned processes, it
interacts with proteins and membrane
lipids (Clinton, 1998). It is synthetized
by plants, photosynthetic bacteria, fungi,
and algae. It can effectively up regulate
the antioxidant response element (ARE),
which induce epoxide hydrolase 1
(EPHX1), superoxide dismutase-1 (SOD-
1), and catalase (CAT).


In terms of biosynthetic pathway, it derives
from the carotenoid pathway. This family of
compound is represented by: -carotein, -
carotein present in yellow-orange vegetables
and fruits, -cryptoxanthin present in orange
fruits, lutein present in dark green vegetables
and lycopene present in tomatoes (Rao et al.,
2007).
Lycopene is deeply bound to macromolecules in
the food matrix, thus its bioavailability is
relatively poor. Cooking is one of the methods
by which bioavailability goes up (Bremeen et
al., 2008). As a matter of fact, ketchup contains
as much as 2 times more lycopene than fresh
tomato (Clinton, 1998).

Once ingested, it reaches the small intestine where it is solubilized by micelles
through passive transport. Then they get incorporated in chylomicrons, as
happens with other carotenoids they leave the intestinal mucosa to reach the
bloodstream where they can be found primarily in LDL. Once bloodstream-borne it
can reach different tissues such as: cardiac, muscular, gonads, osseous, etc. This
process also affects the racemic ratio of the compound. Breemen et al. reported
that even when 100% trans-lycopene was administered, after absorption and
reaching the bloodstream the racemic concentration was 50% for trans-lycopene,
or even as low as 22.7% depending on the tissue type. Gustin et al. reported a half-
Figure 3. Biological roles of Lycopene.
Figure 4. Carotenoid family structures.
life of 28-62 h in a dosage dependent manner (10 to 120 mg). The maximum total
lycopene concentration was reached in 16-33 h with maximum levels of 0.075 to
0.210 M.

Mean serum concentrations of lycopene in different populations range from 50 to
900 nM/L, although inter-individual variation is typically very large, with standard
deviation usually in the range of 50% of the mean (Clinton, 1998). One 6-week
study of volunteers fed 180 mg tomato juice that contained 12 mg lycopene
reported that serum concentrations increased by only 34 nM / L (Micozzi et al.,
1992). In a 15 mg/day for 3 weeks treatment it was shown to decrease the levels
of PSA (Prostate specific antigen) as well as the growth of prostate cancer in newly
diagnosed patients (Rao et al., 2007). Whereas a 15 mg/day for 8 weeks treatment
significantly decreases systolic blood pressures from the baseline value of 144
mmHg to 134 mmHg in mildly hypertensive subjects (Clinton, 1998).

In vitro studies have shown two main groups
of metabolic byproducts: cleavage products
and oxidation products. The detection of 2,6-
cyclolycopene-1,5-diols A and B in human
serum, milk and organs was reported. These
compound were identified as apo-8-
lycopenal and apo-10-lycopenal.

Hu et al. demonstrated that carotene-9,10-
monooxygenase (CMO2) can catalyze the
conversion of 5-cis- and 13-cis-lycopene but
not all-trans-lycopene to apo-10-carotenal.
Furthermore, apo-10-carotenal and a few
other oxygenated derivatives of lycopene
have been identified in vivo following
lycopene administration to animals.

Liu et al. reported that lycopene selectively accumulates in androgen-sensitive
prostate cells and is translocated to the nuclear membrane and nuclear matrix.
This is probably responsible for its anti-cancer activity mainly for prostate cancer.
For example, lycopene can up regulate the antioxidant response element in
prostate cells and thereby induce them to synthesize enzymes that protect against
electrophilic metabolites and oxidative stress. In addition, lycopene can induce
apoptosis in cancer cells and inhibit their proliferation by producing cell cycle
arrest. At 0.33.0 M lycopene induces apoptosis in a concentration dependent
manner in LNCaP cancer cell line (human prostate cancer). Anti-metastatic activity
of lycopene has also been shown in models of prostate cancer. The growth of
Hep3B human hepatoma cells was inhibited 2050% (cell cycle arrest) at
physiologically significant concentrations as low as 0.2 M. Not as effective as in
colon cancer, where it inhibited cell proliferation in HT-29 (human colon cancer
cells) with EC50 value of 10 M.

Figure 5. Some of the mammalian byproducts of lycopene metabolism.

The remarkable ROS quenching capacity of lycopene surpasses that of many
carotenoids. Which relies primarily on the number of conjugated double bonds,
this accounts for the exceptionally high capacity exhibited by this carotenoid. It has
been categorized as the most potent quencher of singlet oxygen and free radicals
among the carotenoids, this activity has been observed experimentally both in
vitro and in vivo.

Even when its antioxidant activity has been correlated with a cancer risk
reduction, its therapeutical use has not been completely elucidated nor approved
by the FDA; some controversy surrounds the topic. Perhaps the most important
studies that are expected to be reported during the next several years will be
Phase II clinical trials that are placebo-controlled, randomized and double blind.
Although some phase I and II studies have been published that establish the safety
of lycopene supplementation, these studies do not address definitively the
potential efficacy of lycopene as a chemoprevention agent.
Currently, there is not enough information on: potential risks, dose-response
relationships, appropriate timing of intake relative to stages of disease processes,
etc. Still, lycopene represents a potential anti-cancer adjuvant because of its
antioxidant capacities. But principally it embodies a prevention drug for the
overall oxidative process of the body, which can lead to several diseases such as
cancer. In healthy subjects 57 mg/day is sufficient to maintain circulating levels
of lycopene to combat oxidative stress and prevent chronic diseases.

References:
Clinton, S. K. 1998. Lycopene: chemistry, biology, and implications for
human health and disease. Nutrition reviews, 56 (2), pp. 35--51.
Gustin, D. M., Rodvold, K. A., Sosman, J. A., Diwadkar-Navsariwala, V.,
Stacewicz-Sapuntzakis, M., Viana, M., Crowell, J. A., Murray, J., Tiller, P. and
Bowen, P. E. 2004. Single-dose pharmacokinetic study of lycopene delivered
in a well-defined food-based lycopene delivery system (tomato paste-oil
mixture) in healthy adult male subjects. Cancer Epidemiology Biomarkers &
Prevention, 13 (5), pp. 850--860.
Hu, K., Liu, C., Ernst, H., Krinsky, N. I., Russell, R. M. and Wang, X. 2006. The
biochemical characterization of ferret carotene-9, 10-monooxygenase
catalyzing cleavage of carotenoids in vitro and in vivo. Journal of Biological
Chemistry, 281 (28), pp. 19327--19338.
Liu, A., Pajkovic, N., Pang, Y., Zhu, D., Calamini, B., Mesecar, A. L. and Van
Breemen, R. B. 2006. Absorption and subcellular localization of lycopene in
human prostate cancer cells. Molecular cancer therapeutics, 5 (11), pp.
2879--2885.
Micozzi, M. S., Brown, E. D., Edwards, B. K., Bieri, J., Taylor, P. R., Khachik, F.,
Beecher, G. R. and Smith, J. 1992. Plasma carotenoid response to chronic
intake of selected foods and beta-carotene supplements in men. The
American journal of clinical nutrition, 55 (6), pp. 1120--1125.
Rao, A. and Rao, L. G. 2007. Carotenoids and human health. Pharmacological
Research, 55 (3), pp. 207--216.
Van Breemen, R. B. and Pajkovic, N. 2008. Multitargeted therapy of cancer
by lycopene. Cancer letters, 269 (2), pp. 339--351.