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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] .
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