title: The effect of apigenin on cyclophosphamide and doxorubicin genotoxicity in vitro and in vivo.
abstract: The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid, apigenin, alone and in combination with the antitumor drugs, cyclophosphamide and doxorubicin, in vitro and in vivo. Using bacterial reverse mutation inhibition in vitro, with and without metabolic activation, the effect of apigenin (10-400 μg/plate) was studied on genotoxicity induced by cyclophosphamide (800 μg/plate) and by doxorubicin (0.2 μg/plate). Subsequent to a dose-finding study in vivo, CD1 mice were treated with either cyclophosphamide (40 mg/kg, i.p.) or doxorubicin (5 mg/kg, i.p.) with or without co-administration of apigenin (1-100 mg/kg, p.o.). Micronuclei were determined microscopically in blood smears and glutathione peroxidase (GPX), superoxide dismutase (SOD) and total antioxidative status (TAS) in whole blood, erythrocytes and plasma, respectively. Apigenin decreased doxorubicin-induced, but not cyclophosphamide-induced mutagenicity in vitro. In vivo, apigenin caused a statistically significant decrease in micronucleus frequency in response to cyclophosphamide, possibly due to active flavonoid metabolite formation or inhibition of cyclophosphamide metabolic activation. In animals treated with apigenin and doxorubicin, a significant decrease in micronucleus frequency was not observed, probably due to interindividual variability. No changes in GPX, SOD or TAS were observed in response to either cytotoxic agents or the flavonoid, possibly due to limited metabolic transformation of the drugs at the doses used. The results of the present study provide further evidence for the chemo-preventative properties of apigenin.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Zagreb, Croatia. ana.bokulic@gmail.com
authors.forename: Ana
authors.initials: A
authors.lastname: Bokulić
authors.forename: Verica
authors.initials: V
authors.lastname: Garaj-Vrhovac
authors.forename: Karmen
authors.initials: K
authors.lastname: Brajsa
authors.forename: Koraljka
authors.initials: K
authors.lastname: Ethurić
authors.forename: Ines
authors.initials: I
authors.lastname: Glojnarić
authors.forename: Kristina
authors.initials: K
authors.lastname: Situm
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000737:chemistry; D047310:Apigenin / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000633:toxicity*; D004249:DNA Damage; D004317:Doxorubicin / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000097:blood; D051379:Mice; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium; D013482:Superoxide Dismutase / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D047310:Apigenin; D004317:Doxorubicin; D003520:Cyclophosphamide; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase