Prominent Stereo-selectivity of NNAL Glucuronidation in Upper Aerodigestive Tract Tissues

Tobacco specific nitrosamines (TSNAs) are among the most potent carcinogens found in cigarettes and smokeless tobacco products. Decreases in TSNA detoxification, particularly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been associated with tobacco-related cancer incidence. NNK is metabolized by carbonyl reduction to its major carcinogenic metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is detoxified by glucuronidation at the nitrogen within the pyridine ring or at the chiral alcohol to form four glucuronide products: (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc, (R)-NNAL-N-Gluc, (S)-NNAL-N-Gluc. Stereo-selective NNAL-Gluc formation and the relative expression of NNAL-glucuronidating UGTs (1A4, 1A9, 1A10, 2B7, 2B10, 2B17) were analyzed in 39 tissue specimens from the upper aerodigestive tract [esophagus (n=13), floor of mouth (n=4), larynx (n=9), tongue (n=7), and tonsil (n=6)]. All tissue types preferentially formed (R)-NNAL-O-Gluc in the presence of racemic-NNAL; only esophagus...