Stereoselective metabolism and tissue retention in rats of the individual enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), metabolites of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is reduced to its main metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in a reaction that is both stereoselective and reversible. (S)-NNAL has been shown to be equivalent to NNK in carcinogenic potency, and significantly more potent than (R)-NNAL. It was hypothesized that stereoselective differences in metabolism or tissue distribution contributed to the difference in carcinogenicity between the enantiomers. The individual NNAL enantiomers were therefore administered to bile duct-cannulated rats. Male Fisher F344 rats received i.v. doses of either (R)-NNAL (n=10) or (S)-NNAL (n=9) and bile, urine, blood and tissue samples were collected over 24 h. (R)/(S)-NNAL and metabolites were quantified by HPLC and radioflow detection. NNAL was also collected from the HPLC and silylated, and the two NNAL enantiomers were separated by chiral GC-TEA. (S)-NNAL had a much larger tissue distribution (Vss=1792 ± 570 ml) than did (R)-NNAL (Vss=645 ± 230 ml). Overall, (R)-NNAL tended to enter detoxification pathways, particularly glucuronidation, while reversible metabolism of (S)-NNAL to NNK was favored. For example, after (R)-NNAL administration, ∼50% of the dose was excreted as (R)-NNAL-Gluc in bile and urine, and <5% was excreted as NNK or NNK metabolites. In contrast, only 10% of an (S)-NNAL dose was excreted as a glucuronide, while almost 20% of the (S)-NNAL dose was excreted as NNK or NNK metabolites. In tissues, particularly the lung, (S)-NNAL appeared to be stereoselectively retained. These findings suggest that the difference in carcinogenicity between the NNAL enantiomers may be attributed to stereoselective differences in tissue distribution and excretion.

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