Modulatory effects of the antioxidant ascorbic acid on the direct genotoxicity of doxorubicin in somatic cells of Drosophila melanogaster

Abstract

In this study two different crosses involving the wing cell markers mwh and flr 3 (standard (ST) cross and high bioactivation (HB) cross, the latter being characterized by a high constitutive level of cytochrome P450 which leads to an increased sensitivity to a number of promutagens and procarcinogens) were used to investigate the modulatory effects of ascorbic acid (AA) combined with the antitumor agent doxorubicin (DXR) in Drosophila melanogaster. We observed that the two different concentrations of AA (50 or 100 mM) had no effect on spots frequencies, while DXR treatments (0.2 or 0.4 mM) gave positive results for all types of spots, when compared to negative control. For marker-heterozygous (MH) flies, a protective effect was observed with the lower concentration of AA (50 mM) that was able to statistically decrease the frequency of spots induced by DXR (0.2 mM), while an enhanced frequency of spots induced by DXR was observed with the higher concentration of AA (100 mM), when compared to DXR treatment (p < 0.05). These results suggest that AA may interfere with free radicals generated by DXR and with other possible reactive metabolites. The efficiency of AA in protecting the somatic cells of D. melanogaster against mutation and recombination induced by DXR is dependent on the dose used and the protection is directly related to the activity of cytochrome P450 enzymes.

Protection by Panax ginseng C.A. Meyer against the genotoxicity of doxorubicin in somatic cells of Drosophila melanogaster

“…In addition to its mutagenic activity, DOX also has recombinogenic activity so that the frequency of twin spots reflected DOX-induced somatic recombination. These findings agree with other reports and show that DOX selectively induces homologous recombination when compared with mutational events in D. melanogaster somatic cells (Lehmann et al, 2003;Costa and Nepomuceno, 2006;Fragiorge et al, 2007;Valadares et al, 2008).…”

“…The main mechanisms of action proposed for DOX include the inhibition of topoisomerase II, DNA intercalation, free radical formation, reductive bioactivation of the quinine ring to a semiquinone radical, DNA alkylation and cross-linking (Gewirtz, 1999;Ramji et al, 2003;Navarro et al, 2006). These mechanisms can result in the cleavage of DNA which, if not repaired, may lead to mutations and chromosomal aberrations in tumors as well as in healthy cells (Antunes and Takahashi, 1998;Gentile et al, 1998;Islaih et al, 2005;Antunes et al, 2007;Costa and Nepomuceno, 2006;Fragiorge et al, 2007;Valadares et al, 2008).…”

“…This one-generation test, which is very efficient and sensitive, is based on the ability of fruit flies to metabolize certain procarcinogens to their reactive metabolites and has been used to study the genotoxicity and antigenotoxicity of various natural compounds (Idaomar et al, 2002;Laohavechvanich et al, 2006;Silva et al, 2006;Fragiorge et al, 2007;Mezzoug et al, 2007;Tellez et al, 2007;Valadares et al, 2008). The wing SMART is based on the principle that a loss of heterozygosity leads to the expression of recessive marker genes in larval imaginal disk cells, thereby yielding clones of mutant cells that can be identified as mosaic spots on the wings (Graf et al, 1984(Graf et al, , 1998.…”

Modulatory effect of Palicourea coriacea (Rubiaceae) against damage induced by doxorubicin in somatic cells of Drosophila melanogaster

“…Comparing the clone induction frequency in both genotypes obtained with DXR alone, we observed that 9.97% of the mutant clones produced in ST flies were a result of mutation and 90.03% of recombination, and that 17.89% of the spots induced in HB flies occurred due to mutation and 82.11% to recombination. The strong recombinogenic activity of DXR in somatic cells of D. melanogaster has been previously reported by Lehmann et al (2003), Costa and Nepomuceno (2006) and Fragiorge et al (2007). In ST cross descendants, recombination was responsible for reducing the frequency of spots produced by DXR in combination with 5, 10, and 15 mg/mL AEP by 68.14, 81.82, and 77.72%, respectively.…”

Antigenotoxic effects of Mandevilla velutina (Gentianales, Apocynaceae) crude extract on cyclophosphamide-induced micronuclei in Swiss mice and urethane-induced somatic mutation and recombination in Drosophila melanogaster

“…melanogaster are versatile and sensitive in vivo eukaryotic systems for the determination of genotoxic and antigenotoxic activity of chemical compounds and complex mixtures (Graf et al, 1998;Idaomar et al, 2002;Silva et al, 2006;Fragiorge et al, 2007;Pantaleão et al, 2007;Téllez et al, 2007).…”