Aristoloxazines Are Highly Cytotoxic and Form DNA Adducts in Human Cells and Mouse Organs.

Aristoloxazines (AXs) represent a newly identified class of neurotoxins and genotoxins found in plants of the Asarum and Aristolochia families, many of which are traditionally used as herbal remedies. Recently, they have also been detected in high abundance in some herbal plant cultivation fields. We revealed in this study that AX-C and AX-A exhibit significant cytotoxicity in both HEK293 and L02 cells, with LC50s < 5 μM. Furthermore, AX-C generates adducts that, based on mass spectral and chromatographic data, are identical or very similar to those of the well-characterized human carcinogen aristolochic acid I (AA-I), in DNA samples from both cultured human cells and internal organs of mice exposed to AXs. Given that AA-I DNA adducts have been shown to induce high frequencies of AT → TA transversions and are believed to be responsible for the observed toxicity of AA-I, our results highlight a previously unrecognized group of potent genotoxins that pose an ongoing risk to human health.