Safrole-like DNA adducts in oral tissue from oral cancer patients with a betel quid chewing history

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Abstract
Betel quid (BQ) chewing has been associated with an increased risk of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). Piper betle inflorescence, which contains 15 mg/g safrole, is a unique ingredient of BQ in Taiwan. Chewing such prepared BQ may contribute to safrole exposure in human beings (420 μM safrole in saliva). Safrole is a known rodent hepatocarcinogen, yet its carcinogenicity in human beings is largely undetermined. In this study, using a 32 P-post-labeling method, we have found a high frequency of safrole-like DNA adducts in BQ-associated OSCC (77%, 23/30) and non-cancerous matched tissue (NCMT) (97%, 29/30). This was in contrast to the absence (< 1/10 9 nucleotides) of such adducts in all of non-BQ-associated OSCC and their paired NCMT ( P < 0.001). Six of seven OSF also exhibited the same safrole-like DNA adduct. The DNA adduct levels in OSF and NCMT were significantly higher than in OSCC ( P < 0.05). Using co-chromatography and rechromatography techniques, we further demonstrated that these adducts were identical to synthetic safrole–dGMP adducts as well as DNA adducts from 1′-hydroxysafrole-treated HepG2 cells. These results suggest that safrole forms stable safrole–DNA adducts in human oral tissue following BQ chewing, which may contribute to oral carcinogenesis.

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