Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Biochemistry

Use of cyclophosphamide (CPA) or fludarabine as chemotherapeutic agents is associated with deleterious side effects including pulmonary toxicity and urotoxicity or myelosuppression, respectively. Avocado, Persea americana Mill. is a widely consumed fruit in many countries for its nutritional and medicinal benefits. In the present study, we investigated the modulating effect of avocado fruit extract (AE) on some metabolizing enzymes involved in the activation and detoxification of CPA and fludarabine. Three phases of CPA-induced urotoxicity and pulmonary toxicity were studied; 2, 7 and 28 days after a single i.p. injection at a dose of 150 mg/kg. Fludarabine was injected (5 mg/kg/day, i.p.) for five consecutive days and tested for its myelosuppression 12 days post first injection. Cyclophosphamide induced acute elevation followed by late reduction in cytochrome P450 2B6 (CYP2B6) level in hepatic microsomes and significantly suppressed bladder and lung glutathione-S-transferase (GST) activity. Furthermore, CPA elevated bladder blood content, lung myeloperoxidase activity, DNA and hydroxyproline contents. Fludarabine produced a significant decrease in deoxycytidine kinase (dCK) and cytosolic nucleotidase II (cN-II) levels. In addition, fludarabine administration reduced total leukocytic and lymphocytic count as well as DNA polymerase and ribonucleotide reductase levels. Avocado extract administration (900 mg/kg/day p.o.) for 7 days prior to CPA and fludarabine exposure and its continuation for 2, 7 and 28 days post CPA and 12 days post first fludarabine injection, ameliorated all CPA and fludarabine induced derangements in spite of variable effects on metabolizing enzymes. Avocado extract administration suppressed CYP2B6 level, augmented GST activity of CPA treated rats and restored the level of both dCK and cN-II of fludarabine treated rats. In conclusion, these results show that AE plays a protective role against CPA and fludarabine-induced toxicity by regulating drug metabolizing enzymes and exerting antioxidant activity

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