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Biosynthesis of a Flavonol from a Flavanone by Establishing a One-pot Bienzymatic Cascade
Published on: August 14, 2019
Flavonoids inhibit genetic toxicity produced by carcinogens in cells expressing CYP1A2 and CYP1A1
S Lautraite1, A C Musonda, J Doehmer
1School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
Abstract:
The effects of the flavonoids quercetin, apigenin and chrysin (10 microM) on the genetic toxicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and benzo[a]pyrene (BaP) was investigated at sub-cytotoxic concentrations in Chinese hamster V79 cells expressing human or rat cytochromes P450. In V79 r1A2-NH and V79 h1A1-MZ cells, none of the flavonoids increased DNA strand breaks (SB) (measured by the Comet assay) or produced detectable DNA adducts (measured by 32P-post-labelling). Neither IQ nor BaP produced DNA damage in the absence of expressed CYP1A2 or CYP1A1, respectively. DNA damage measured as SB and DNA adducts was detectable in V79 r1A2-NH cells expressing rat CYP1A2 when treated with IQ (2.5-50 microM) and this was inhibited by quercetin. Likewise, DNA damage (SB and DNA adducts) was elevated in V79 h1A1-MZ cells expressing human CYP1A1 when treated with BaP (0.1-0.5 microM) and this was inhibited by chrysin and apigenin, but not by quercetin. The specificity of CYP1A1 inhibition by chrysin and apigenin and CYP1A2 inhibition by quercetin was confirmed by ethylresorufin O-deethylase assay.
Insights
Flavonoids quercetin, apigenin, and chrysin were tested for their effects on the genetic toxicity of IQ and BaP in cells expressing specific P450 enzymes. Quercetin inhibited IQ-induced DNA damage, while chrysin and apigenin inhibited BaP-induced damage.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Flavonoids are plant-derived compounds with potential health benefits.
- Certain flavonoids can modulate the activity of cytochrome P450 enzymes.
- Genetic toxicity of environmental mutagens like IQ and BaP is often mediated by P450 metabolism.
Purpose of the Study:
- To investigate the modulatory effects of quercetin, apigenin, and chrysin on the genetic toxicity induced by IQ and BaP.
- To determine the role of specific cytochrome P450 enzymes (CYP1A1 and CYP1A2) in mediating this toxicity and the inhibitory potential of these flavonoids.
Main Methods:
- Chinese hamster V79 cells expressing human CYP1A1 (V79 h1A1-MZ) or rat CYP1A2 (V79 r1A2-NH) were used.
- Genetic toxicity was assessed by measuring DNA strand breaks (Comet assay) and DNA adducts (32P-post-labelling).
- Flavonoid effects were evaluated at sub-cytotoxic concentrations, and enzyme specificity was confirmed using ethylresorufin O-deethylase assays.
Main Results:
- IQ and BaP induced DNA damage (strand breaks and adducts) only in cells expressing the respective P450 enzymes (CYP1A2 for IQ, CYP1A1 for BaP).
- Quercetin significantly inhibited IQ-induced DNA damage in V79 r1A2-NH cells.
- Chrysin and apigenin inhibited BaP-induced DNA damage in V79 h1A1-MZ cells, whereas quercetin did not.
Conclusions:
- Quercetin specifically inhibits CYP1A2-mediated genotoxicity of IQ.
- Chrysin and apigenin specifically inhibit CYP1A1-mediated genotoxicity of BaP.
- These findings highlight the potential of specific flavonoids to mitigate the risks associated with exposure to certain environmental mutagens through P450 enzyme modulation.
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