Aristolochic acid induces 6-thioguanine-resistant mutants in an extrahepatic tissue in rats after oral application.

The mutagenic activity of the natural plant product aristolochic acid (AA) was tested in the Granuloma Pouch Assay, which detects gene mutations induced in a subcutaneous granuloma tissue of rats. After direct exposure of the target tissue, AA induced high frequencies of mutants at a relatively low cytostatic/cytotoxic level. AA was more potent that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at equimolar doses. After oral application of AA, a dose-dependent mutagenic activity was seen. In contrast a very weak and inconsistent mutagenic effect was seen after systemic application of MNNG. These observations suggest that after oral application AA is not detoxified efficiently and can exert its mutagenic activity in extrahepatic tissues whereas MNNG is detoxified to a large extent at the site of administration.