Antigenotoxic activity of apigenin, naringenin, and hesperetin in vivo: tissue specificity of effects

Background: Data on tissue specificity and the range of antigenotoxic activities help target the practical applications of antigenotoxic agents. This study evaluated the tissue specificity of the antigenotoxic activity of the natural flavonoids apigenin, naringenin, and hesperetin against DNA-damaging effects of temozolomide and cytogenetic effects induced by genotoxicants with diverse mechanisms of action.

Methods: Apigenin (5, 25, and 50 mg/kg), naringenin, and hesperetin (25, 50, and 100 mg/kg) were administered orally three times before genotoxicant injection. In a separate experiment, apigenin was administered 1 hour after temozolomide injection. Genotoxicants (temozolomide (50 mg/kg), cyclophosphamide (20 mg/kg), methyl methanesulfonate (80 mg/kg), and dioxidine (250 mg/kg)) were administered intraperitoneally. DNA damage was assessed using the comet assay in bone marrow, liver, kidney, brain, and rectum, while chromosomal aberrations were evaluated in bone marrow cells.

Results: Apigenin reduced temozolomide-induced DNA damage in bone marrow (52–66%), liver (31–65%), kidney (50%), and rectum (100%), but not in brain. At all tested doses, apigenin decreased the frequency of “hedgehog” comets in kidneys. Naringenin exhibited antigenotoxic effects by reducing DNA damage in bone marrow (48–62%), brain (26–44%), and rectum (49–54%), but not in liver or kidneys. Hesperetin demonstrated antigenotoxicity in bone marrow (23%), kidneys (29–33%), brain (23–42%), and rectum (32–47%).

In the cytogenetic study, apigenin dose-dependently reduced temozolomide-induced effects by 49–73%, naringenin by 49–75%, and hesperetin by 39–55%. In the post-treatment regimen, apigenin (5–50 mg/kg) reduced temozolomide-induced effects by 47–51%. Additionally, apigenin (5 and 25 mg/kg) significantly mitigated the cytogenetic effects of dioxidine, while at 25 mg/kg, it also reduced those induced by cyclophosphamide and methyl methanesulfonate. Naringenin (50 and 100 mg/kg) attenuated the effect of cyclophosphamide (43–71%) but not dioxidine.

Conclusions: Apigenin, naringenin, and hesperetin exhibit tissue-specific antigenotoxic activity against temozolomide. Apigenin and naringenin also can reduce cytogenetic damage induced by genotoxicants with diverse mechanisms.