الفهرس 
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Abstract
DEN is a potent hepatocarcinogenic nitrosamine present in tobacco smoke, polluted water, cosmetics, cured meat products, and pharmaceutical agents. DEN-induced HCC is an accepted and widely-used experimental model of hepatocarcinogenesis in humans.
A two-stage model in which the initiation by a genotoxic compound is followed by a promotion phase is often used for inducing hepatocarcinogenesis. DEN can be used as an initiator and 2AAF as a promotor. In the recent times, natural products have been used to prevent the toxicities induced by chemicals, drugs and carcinogenic xenobiotics.
The present study aims to assess the preventive effects of quercetin and naringenin on DEN/2AAF-induced carcinogenicity and hepato-nephrotoxicity in Wistar rats.
The adult Wistar rats of this study were allocated into four groups six for each designed as follow:
group I (The group was kept as a normal group): The included rats of this group received, by i.p. route, the equivalent volume of saline (0.9% NaCl) at the beginning of experiment two times per one week for 2 weeks. Starting from the 3rd week, the rats received the equivalent volume of 1% tween 80, by oral gavage, four times per week for three weeks. This group was also orally given the equivalent volume 1% CMC (1 % w/v) as vehicle every other day till the end of the experiment.
group II (DEN/2AAF-administered group was kept as control): The animals within this group were given i.p. injection of DEN (150 mg/kg b.w./week for two weeks) dissolved in 0.9% saline. One week after the last injection of DEN, 2-AAF (20 mg/kg b.w.) (de Lujan Alvarez et al., 2002) in 1 % tween 80 was administered orally by gavage four days per week for three weeks, then rats were sacrificed after 20 weeks from the beginning of the experiment.
group III (DEN/2AAF-administered group-treated with quercetin): This group was given DEN/2AAF as group II and was orally treated with quercetin at a dose of 10 mg/kg b.w. (Zargar et al., 2016) dissolved in 5 ml of 1% CMC (1 % w/v) and was administered to rats by oral gavage every other day for 20 weeks from the beginning of the experiment.
group IV (DEN/2AAF-administered group-treated with naringenin): This group was given DEN/2AAF as group II and was orally treated with naringenin at a dose of 10 mg/kg b.w. (Roy et al., 2015) dissolved in 5 ml of 1% CMC (1 % w/v) and was administered to rats by oral gavage every other day for 20 weeks from the beginning of the experiment.
In the present study, the animals treated with DEN/2AAF showed a significant liver damage manifested by the increased serum ALT, AST, ALP and γGT activities and total bilirubin level as well as the lowered total protein and albumin levels. The treatment of DEN/2AAF-administered rats with quercetin and naringenin led to marked improvements in these liver function parameters in serum.
The obtained data also revealed a significant increase of AFP, CEA and CA19.9 levels in DEN/2AAF-administered rats. The treatment of DEN/2AAF-administered animals with quercetin and naringenin successfully ameliorated these changes.
The administration of DEN and 2AAF increased IL-1β and COX-2 mRNA expressions but the treatments of DEN/2AAF-administered rats with quercetin and naringenin improved these alterations. On the other hand, the mRNA expression of IL-4 was decreased in DEN/2AAF-administered group, while the treatment of these animals with quercetin and naringenin increased its expression. There were also decreases in P53 and Bcl2 mRNA expressions in rats administered DEN and 2AAF but these markers were increased in the DEN/2AAF-administered rats treated with quercetin and naringenin.
These biochemical changes are concomitant with the liver histological ones that include changes like hepatocellular carcinoma cells, periportal inflammatory cells infiltration, steatosis, hyperchromatic karyomegalic nuclei of tubular cells, bile duct cystadenoma and inflammatory cells infiltration. The treatment of these animals with quercetin and naringenin successfully prevented most of these biochemical and histological alterations.
Concerning liver oxidative stress the elevated liver LPO and NO levels were potentially decreased in the DEN/2AAF-adminstered rats due to quercetin and naringenin administration. Regarding antioxidant defense system, the depleted glutathione content as well as the decreased glutathione peroxidase, glutathione-S-transferase, catalase and superoxide dismutase activities of DEN/2AAF-administered rats were potentially increased as a result quercetin and naringenin treatments.
Nephrotoxicity-induced by DEN/2AAF was evidenced by elevations in serum biochemical variables related to kidney dysfunction, creatinine, urea and uric acid concentrations. In addition, renal injury induced by DEN/2AAF-administration was confirmed by the histological changes and several lesions including vacuolar degenerative changes of renal tubules, karyomegally of some hyperchromatic nucli and cytoplasmic vacuolation of epithelial lining renal tubules while the treatment of DEN/2AAF-administered rats with quercetin and naringenin decreased the elevated levels of serum creatinine, urea and uric acid levels and successfully amended the renal histological perturbations.
Regarding kidney oxidative stress the elevated kidney LPO and NO levels were potentially decreased in the DEN/2AAF-adminstered rats due to quercetin and naringenin administration. Moreover, a striking decrease in the antioxidants in DEN/2AAF-exposed rats elicits strong evidence for the involvement of oxidative damage in DEN/2AAF-induced nephrotoxicity. The depleted kidney glutathione content was significantly increased in the case of quercetin and naringenin treatments. Moreover, the decreased activities of kidney SOD, CAT, GPx and GST were significantly alleviated as a result of quercetin and naringenin treatments as compared to DEN/2AAF-administered rats.
In conclusion, the possible preventive effects of quercetin and naringenin on DEN/2AAF-induced carcinogenesis and hepato-nephrotoxicity may be explained on the basis of oxidant-antioxidant system management, regulation of the inflammatory status as well as initiating the apoptotic pathway. However, clinical studies are required to assess the safety and the efficacy of these agents in human beings.