Human cervical tissue metabolizes the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, via alpha-hydroxylation and carbonyl reduction pathways

Abstract

Bovine papillomavirus type 4 (BPV-4) infects the upper alimentary canal of cattle causing benign papillomas which can progress to squamous carcinomas in cattle grazing on bracken fern (BF). We have previously shown that quercetin, a well characterized and potent mutagen found in BF, causes cell cycle arrest of primary bovine cells (PalF), but that a single exposure to quercetin can cause full oncogenic transformation of PalF cells partially transformed by BPV-4. Here we show that cell cycle arrest correlates with an increase in p53 protein levels and transcriptional activity. However, in cells transformed but non-tumorigenic, p53 protein is elevated and transcriptionally activated in response to quercetin or other DNA damaging stimuli, but the cells bypass quercetin-induced G₁ arrest likely due to E7 expression. In transformed tumorigenic cells, p53 is elevated in response to quercetin but its transcriptional activity is inhibited due to mutation, and the cells fail to stop in G₁ in the presence of quercetin.