Aristolochic acid (AA-I) is a powerful nephrotoxin and human carcinogen. Human sulfotransferases were reported by Meinl et al (2006) to be involved in the metabolic activation of AA-I, while Stiborova et al (2011), using a different system, showed that only NQO1 is involved. We resolved this apparent discrepancy by developing a novel synthesis for N-hydroxyaristolactam and its conjugated derivatives then tested their ability to react with duplex DNA under physiological conditions to form dA and dG adducts. As with most bulky forms of DNA damage, dA-aristolactam adducts normally would be excised by global genomic nucleotide excision repair. However, the structure of dA- aristolactam in adducted DNA precludes recognition by XPC/R23B, the initial step in global genomic repair, while transcription-coupled repair of this lesion is unaffected, resulting in persistence in human tissues and a mutational pattern with marked strand bias in mutated TP53, FGFR3 and HRAS.

Metabolic activation of aristolochic acid and mechanism of repair of aristolactam-DNA adducts in human cells

244th National Meeting (2012)

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