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Page 12 of 16 Bhatia et al. Hepatoma Res 2018;4:9 I http://dx.doi.org/10.20517/2394-5079.2018.04

hepatic tissue as observed by the changes in HEF, percentage counts in the liver at different time intervals,
T and T 1/2 peak . Control and LycT animals showed the normal uptake, efficient hepatic extraction and
peak
rapid excretion from the liver. However, a significant deviation from the normal pattern of radioactivity as
observed in NDEA animals confirmed the physiological alterations in hepatic tissue. The delay in hepatic
[34]
uptake in NDEA animals may be due to severe hepatocellular dysfunction. Neyt et al. have also reported
the delayed uptake due to the dysfunction of various Oatp transporters located on hepatocytes. The retention
of radiotracer activity in the liver of NDEA mice up to 60 min showed marked impairment in the excretion
of the activity. This may be due to the biliary obstruction induced by NDEA which was also evidenced
by the inability to calculate T value in case of NDEA animals. We have previously reported the delay in
1/2
hepatic excretion in the case of DMBA induced hepatotoxicity . Joseph et al. observed the involvement
[35]
[36]
99m
of inflammation in delaying the hepatic excretion of Tc-mebrofenin. Similarly, LycT administration to
NDEA insulted animals also showed delayed uptake but the clearance of the activity at 60 min showed the
protective effect of LycT against hepatocarcinogenesis. Deshpande et al. observed the increased clearance
[37]
of Tc-mebrofenin upon administration of dietary turmeric extract to rats exposed to D-galactosamine
99m
HCl. Our laboratory also observed the ameliorative effect of Azadirachta indica against DMBA induced
hepatotoxicity by efficient clearance of mebrofenin .
[35]
During tumor progression, cells generally demand more oxygen than is available for its growth, which results
in the creation of hypoxia. Continued hypoxia leads to the adaptation of various genomic and proteomic
alterations and results in the aggressive and malignant tumor phenotype. This may further causes reduced
oxygen transport throughout the body due to the alterations in various hematological markers. NDEA
exposed mice showed a marked decline in the levels of Hb, RBC, platelets and lymphocytes as compared
to control mice. In addition to this, a significant enhancement in the neutrophils and WBC counts were
observed upon NDEA exposure. The reduction in Hb and RBC suggested the occurrence of anemia in tumor
bearing mice. This may be due to the increased oxidative stress induced by excessive ROS which causes
the oxidative destruction of mature erythrocytes or inhibiting its production. This can also be evidenced
by a decline in GSH and elevation in LPO levels on NDEA treatment . A marked enhancement in WBC
[38]
counts may reflect the activation of an immune system to fight against invading particles . This was further
[39]
confirmed by the release of various cytokines by activated kupffer cells and accumulation of neutrophils in
hepatic cells as discussed above. Histopathological examination also supported the infiltration of leukocytes
in hepatic tissue upon NDEA administration. The diminished platelets count may apparently be due to the
decreased production of thrombopoietin hormone by damaged liver cells. The decrease in lymphocytes and
enhanced neutrophil counts might suggest the decrease in efficiency of an immune system to cope up with
the triggered inflammatory cascade . Similar observations were also noticed by Farooq et al. and Gangar
[40]
[41]
[42]
et al. , who also observed the alterations in various hematological parameters in patients suffering from
gastric and forestomach carcinoma respectively. LycT treatment to NDEA insulted mice tends to restore the
levels of these markers which might be attributed to decreased hypoxia and reduction in tumor growth by
an enhancement of apoptosis [18,23] . Several other researchers have also supported the restoration of blood
parameters upon lycopene treatment thus showing its anti-inflammatory potential [43,44] .

Inflammatory cytokines also play a major role in the progression of cancer. Exposure of liver tissue to
certain hepatotoxicants induces the release of pro-inflammatory cytokines by kupffer cells which can
further aggravate the tumor progression by triggering of inflammatory cascade . The current findings
[45]
revealed a marked increase in serum levels of various inflammatory markers, i.e., TNF-α, IL-1β and
IL-6 in tumor bearing mice. Overexpression of these cytokines may provide proliferating signals to the
mutated hepatocytes through the secretion of angiogenesis and metastasis markers. These findings were in
concordance with the report of Abdel-Hamid et al. . Supplementation of NDEA mice with LycT modulated
[46]
the serum levels of these cytokines by inhibiting their production and induction of apoptosis thus showing
its anti-inflammatory effect. Literature also supported the amelioration of these inflammatory markers upon
administration of lycopene [47-49] .