Relationship between chromatin bridges in anaphase and chromosomal aberrations induced by TMP+UVA (365 nm) in CHO cells

Botta, Rosanna; Gustavino, Bianca

doi:10.1016/s0027-5107(96)00240-0

Cited by 1 publication

(1 citation statement)

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“…One of them is that chromatin bridges between sister chromatids may reveal the presence of cross-links between DNA strands. Due to the presence of a strong mechanical traction during anaphase, covalently bound chromatids can give rise to such anaphase chromatin bridges (Botta and Gustavino 1997;Rizzoni et al 1993). In our previous study, we found that diester PAs induced DNA cross-links, but the monoester europine did not (Hadi et al 2021).…”

Section: Discussionmentioning

confidence: 72%

Genotoxicity of pyrrolizidine alkaloids in metabolically inactive human cervical cancer HeLa cells co-cultured with human hepatoma HepG2 cells

2022

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Pyrrolizidine alkaloids (PAs) are secondary plant metabolites, which can be found as contaminant in various foods and herbal products. Several PAs can cause hepatotoxicity and liver cancer via damaging hepatic sinusoidal endothelial cells (HSECs) after hepatic metabolization. HSECs themselves do not express the required metabolic enzymes for activation of PAs. Here we applied a co-culture model to mimic the in vivo hepatic environment and to study PA-induced effects on not metabolically active neighbour cells. In this co-culture model, bioactivation of PA was enabled by metabolically capable human hepatoma cells HepG2, which excrete the toxic and mutagenic pyrrole metabolites. The human cervical epithelial HeLa cells tagged with H2B-GFP were utilized as non-metabolically active neighbours because they can be identified easily based on their green fluorescence in the co-culture. The PAs europine, riddelliine and lasiocarpine induced micronuclei in HepG2 cells, and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Metabolic inhibition of cytochrome P450 enzymes with ketoconazole abrogated micronucleus formation. The efflux transporter inhibitors verapamil and benzbromarone reduced micronucleus formation in the co-culture model. Furthermore, mitotic disturbances as an additional genotoxic mechanism of action were observed in HepG2 cells and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Overall, we were able to show that PAs were activated by HepG2 cells and the metabolites induced genomic damage in co-cultured HeLa cells.

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Section: Discussionmentioning

confidence: 72%