الفهرس 
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Abstract
The present study provides much evidence of the preventive effects of avocado fruit and seed hydroethanolicextracts on DEN/2AAF-induced carcinogenicity, hepatotoxicity and cardio-nephrotoxicity in Wistar rats.
Rats were divided to four groups six for each group and were subjected to the following treatments:
group I (Normal group):The included rats of this group received, by intraperitoneal (i.p.) route, the equivalent volume of saline (0.9% NaCl) at the beginning of experiment for 2 weeks, two times per one week. 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 control group):The animals within this group were given twice, i.p., doses of DEN (150 mg/kg b.w.) dissolved in 0.9% saline at the beginning of experiment. One week after the last injection of DEN, 2AAF (20 mg/kg b.w.) (de Lujan Alvarez et al., 2002) in 1 % tween 80, was administrated orally by gavage four days per week for three weeks. The rats of this group were also orally administered the equivalent volume of 1% CMC (1 % w/v) daily for 20 weeks.
group III (DEN/2AAF-administered group treated with avocado fruit extract): This group was given DEN/2AAF as group II and was orally treated with avocado fruit hydroethanolic extract at a dose of (50 mg/kg b.w.) (OECD, 1993) dissolved in 1% CMC(1 % w/v), every other day till the end of the experiment.
group IV (DEN/2AAF-administered group treated with avocado seed extract):This group was given DEN/2AAF as group II and received a dose of (50 mg/kg b.w.) (OECD, 1993) avocado seed hydroethanolic extract dissolved in 1% CMC(1 % w/v) by oral gavage every other day until the end of the experiment.
In the present study, the animals treated with DEN/2AAF showed hepatocellular carcinoma, as elicited by the increased levels of serum enzymes ALT, AST,ALP, GGT activities and total bilirubin level as well as lowered total protein and albumin levels. The treatment of DEN/2AAF-administered rats with avocado fruit and seed hydroethanolicextracts led to marked improvements in theseliver function parameters in serum.
The obtained data also revealed a significant increase of AFP, CEA and CA 19.9 levels in DEN/2AAF-administered rats. The treatment of DEN/2AAF-administered animals with avocado fruit and seed hydroethanolicextractssuccessfully improved these changes.
The administration of DEN and 2AAF increased COX-2and NF-кB, mRNA expressions but the treatments of DEN/2AAF-administered rats withavocado fruit and seed hydroethanolic extracts improved these alterations.On the other hand, the mRNA expression of P53 and Bcl-2 was decreased in DEN/2AAF-administered group, while the treatment of these animals with avocado fruit and seed hydroethanolic extracts increased the P53 and Bcl-2 mRNA expressions.
Concerning liver oxidative stress and antioxidant defense system, the increase of lipid peroxidation and thedepleted glutathione content as well as the decreased glutathione peroxidase,glutathione-S-transferase and superoxide dismutase activities ofDEN/2AAF-administered rats were potentially decrease of lipid peroxidation and theincrease of glutathione content, glutathione peroxidase,glutathione-S-transferase and superoxide dismutase activities with avocado fruit and seed hydroethanolic extracts as a result treatments.
On the other hand, the liver of DEN/2AAF-administered rats led to histological change that show hepatocellular carcinoma, hyperchromatic karyomegalic nuclei, periportal inflammatory cells infiltration, bile duct cyst adenoma, large hyperchromatic nuclei with more than one prominent nucleolus, prenchaymatous steatosis of haemorrhage and moderately differentiated hepatocellular carcinoma with abundant foci of eosinophilic hepatocytes’ cytoplasm. The treatment of theseanimals with avocado fruit and seed hydroethanolic extracts successfullyprevented most of these biochemical and histological alterations.
Nephrotoxicity-induced by DEN/2AAF was evidenced by elevations in serumbiochemical variables related to kidney dysfunction, creatinine, ureaand uric acid concentrations, while the treatment of DEN/2AAF-administered rats with avocado fruit and seed hydroethanolic extracts decreased the elevated levels of serum creatinine, ureaand uric acid.
Concerning kidney oxidative stress and antioxidant defense system, show decreased glutathione content, glutathione peroxidase, glutathione-S-transferase and superoxide dismutase activities ofDEN/2AAF-administered rats while treatment show increased as a result of avocado fruit and seed hydroethanolic extracts.
In addition, renal injury induced by DEN/2AAF-administration was confirmed by the histological changes including mononuclear leucocytic aggregation, perivascular oedema, vacuolar degenerative changes of the epithelial lining of renal tubules, brown pigments accumulation and few karyomegally nuclei. The treatment of these animals with avocado fruit and seed hydroethanolic extracts successfully improvement the histological alterations.
Cardiotoxicity-induced by DEN/2AAF was evidenced by elevation in serumbiochemical variables related to heart dysfunction such as CK, CK-MB and LDH activities, while the treatment of DEN/2AAF-administered rats with avocado fruit and seed hydroethanolic extracts decreased the elevated of CK, CK-MB and LDH activities.
Regarding heart oxidative stress, a striking decrease in the antioxidants inDEN/2AAF-exposed rats elicits strong evidence for the involvement of oxidativedamage in DEN/2AAF-induced cardiotoxicity. The depleted heart glutathionecontent was significantly increased in the case of avocado fruit and seed hydroethanolic extracts. Moreover, the decreased activities of heart GPx, GST and SOD were significantly increase as a result ofavocado fruit and seed hydroethanolic extracts compared toDEN/2AAF-administered control group.
On the other hand, the heart of DEN/2AAF-administered rats led to histological changesthat include changes like perivascular oedema, intermuscular oedema,degeneration of certain cardiomyocytes and intermuscular haemorrage but heart section of DEN/2AAF-administered rat treated with avocado fruit and seed hydroethanolic extract showed no histopathological changes.
In conclusion, the possible preventive effects of avocado fruit and seed hydroethanolic extracts on DEN/2AAF-inducedcarcinogenesis, hepatotoxicity and cardio-nephrotoxicity may be explained on the basis of oxidant-antioxidant systemmanagement, regulation ofthe inflammatory status as well as initiating theapoptotic pathway. Based on the obtained results, avocado fruit extract has the most potent preventive effect on DEN/2AAF-induced hepatotoxicity and nephrotoxicity, while avocado seed extract has the most potent preventive effect onDEN/2AAF-induced cardiotoxicity.