In Vitro Genotoxicity Assessment of a Novel Resveratrol Analogue, HS-1793

Abstract

Resveratrol has received considerable attention as a polyphenol with various biological effects such as anti-inflammatory, anti-oxidant, anti-mutagenic, anti-carcinogenic, and cardioprotective properties. As part of the overall safety assessment of HS-1793, a novel resveratrol analogue free from the restriction of metabolic instability and the high dose requirement of resveratrol, we assessed genotoxicity in three in vitro assays: a bacterial mutation assay, a comet assay, and a chromosomal aberration assay. In the bacterial reverse mutation assay, HS-1793 did not increase revertant colony numbers in S. typhimurium strains (TA98, TA100, TA1535 and TA1537) or an E. coli strain (WP2 uvrA) regardless of metabolic activation. HS-1793 showed no evidence of genotoxic activity such as DNA damage on L5178Y Tk(+/-) mouse lymphoma cells with or without the S9 mix in the in vitro comet assay. No statistically significant differences in the incidence of chromosomal aberrations following HS-1793 treatment was observed on Chinese hamster lung cells exposed with or without the S9 mix. These results provide additional evidence that HS-1793 is non-genotoxic at the dose tested in three standard tests and further supports the generally recognized as safe determination of HS-1793 during early drug development.

Keywords: Bacterial mutation assay; Chromosomal aberration assay; Comet assay; Genotoxicity; HS-1793; Resveratrol.

Fig. 1.. Synthesis and chemical structure of resveratrol analogs, HS-1793.

Fig. 2.. Cytotoxicity and genotoxicity of HS-1793 by the comet assay in L5178Y Tk^+/− mouse lymphoma cells. (A) The cells were treated with the indicated concentrations of HS-1793 for 4 hr. Cell viability was determined by the MTT assay. Each percent value in treated cells was calculated with respect to that in the untreated control. All samples were run in triplicate and experiments were repeated three times. Results are expressed as percentages of control, and data are means ± standard deviations of three independent experiments. (B) Photomicrograph (400×) of comet in L5178Y Tk^+/− mouse lymphoma cells with or without the S9 mix after a 4 hr exposure to HS-1793.

Fig. 3.. Cytotoxicity and genotoxicity of HS-1793 by chromosomal aberration assay in CHL cells. (A) The cells were treated with the indicated concentrations of HS-1793 for 24 hr. Cell viability was determined by the MTT assay. Each percent value in treated cells was calculated with respect to that in the untreated control. All samples were run in triplicate and experiments were repeated three times. Results are expressed as percentages of control, and data are means ± standard deviations of three independent experiments. (B) Photomicrograph (400×) of chromosomal aberration in CHL cells with or without the S9 mix after a 6 or 24 hr exposure to HS-1793.