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Bhatia et al. Hepatoma Res 2018;4:9 I http://dx.doi.org/10.20517/2394-5079.2018.04 Page 13 of 16

NDEA treatment also exhibited enhanced plasma LPO and reduced GSH levels in comparison to control and
LycT animals. The increase in LPO may be ascribed to the excessive formation of ROS and their diffusion
into the blood by an oxidative deterioration of membrane lipids. Declined GSH levels might be due to the
impairment of antioxidant defense system and increased consumption of GSH by the detoxification system.
Literature also supported the alterations in these oxidative stress markers with the progression of cancer [50,51] .
Interestingly, the reversal of their levels by LycT pretreatment may probably be due to the neutralization of
free radicals and enhancement of xenobiotic detoxification by LycT. The amelioration of oxidative stress by
consumption of tomato enriched diet has also been reported by Dogukan et al. and Gupta et al. .
[52]
[12]
The enhancement in plasma activities of SOD, CAT and GSH-Px were also observed upon NDEA
administration. An elevated SOD activity causes the excessive production of deleterious H2O2 by the
dismutation of superoxide anions which may further be counterbalanced by excess CAT and GSH-Px.
However, complete neutralization of H O may not occur due to the failure of defense system by sufficient
2
2
lipid oxidation which further increases the chances of DNA damage, thus, contributing to a growth
[53]
advantage to the tumorous cell . Our results are in agreement with other reports who found similar
alterations in activities of these enzymes in cancer patients [54,55] . Reduction in the activities of these enzymes
by LycT supplementation to tumor bearing mice showing the antioxidant capability of LycT to scavenge the
free radical formation thus mitigating intracellular oxidative damage. The present results are in harmony
[56]
[44]
with the findings of Ural and Ibrahim who also reported the diminished enzymatic activities on LycT
supplementation.
The increase in GST activity in NDEA intoxicated mice may lead to the excessive utilization of this enzyme
in the detoxification in response to metabolic induction in the tumor cells. These results are in concordance
with the observation of Sadik et al. , who also reported the correlation between the increased GST levels and
[57]
[58]
carcinogenesis. In contrast, Li et al. has observed the decrease in blood GST levels during the development
of HCC. Suppression of GST activity upon LycT supplementation to NDEA afflicted mice indicated the
[57]
protective efficacy of LycT against the induction of oxidative stress. Sadik et al. has also reported the
restoration of GST activity upon consumption of a diet rich in fruits and vegetables. The increased activity
of GSH-Px and decreased levels of GSH may lead to the accumulation of oxidized glutathione (GSSG) which
further cannot be converted to GSH due to the reduction in GR activity upon NDEA treatment. Maffei et al.
[55]
has also reported the drop in plasma GR activity in patients suffering from colorectal cancer. Pretreatment
with LycT to NDEA mice attenuated the decrease in GR activity probably by radical scavenging potential
and increase in GSH level thus maintaining the oxido-reductive balance. Lycopene enriched tomato extract
ameliorates the oxidative stress by maintaining the integrity of cellular membrane thus preserving the
antioxidants levels in the liver cells [12,59] . The activities of various enzymatic and non-enzymatic antioxidants
did not show any alterations between control and LycT mice.

It is evident that LycT supplementation modulated the inflammatory and hematological markers, boosted the
antioxidant system and improved the functional status of hepatic tissue in tumor bearing mice. Data from
the present study and previously published studies reiterate the potential of LycT in delaying the initiation of
HCC which may have significant implications in its overall chemopreventive potential.

DECLARATIONS
Authors’ contributions
Study design: Koul A, Singh B
Data analysis and manuscript preparation: Koul A, Singh B, Bhatia N
Experimental studies: Bhatia N
Literature search: Koul A, Singh B, Bhatia N
Manuscript review: Koul A, Singh B, Bhatia N