Absolute configuration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol formed metabolically from 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone |
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Authors: | Hecht SS; Spratt TE; Trushin N |
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Institution: | University of Minnesota Cancer Center, Minneapolis 55455, USA. |
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Abstract: | 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is an important
metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone (NNK). Using the chiral derivatizing agent, (R)-
(+)-alpha-methylbenzyl isocyanate (R)-(+)-MBIC], previous work has shown
that the enantiomeric ratio of metabolically formed NNAL and its
glucuronide derivative may be species dependent. However, the absolute
configuration of such NNAL has not been previously reported. Synthetically
prepared racemic NNAL was converted to diastereomeric esters by reaction
with (R)-(+)- and (S)-(-)-alpha-methoxy-alpha-
(trifluoromethyl)phenylacetic acid (MTPA) chloride (Mosher's reagent) and
the products were characterized by 1H-NMR. Based on chemical shift data,
the absolute configuration of NNAL in each diastereomeric ester was
assigned. Hydrolysis of (R)-NNAL-(R)-MTPA gave (R)-NNAL. This was converted
to the corresponding carbamate by reaction with (R)-(+)-alpha- MBIC and the
absolute configurations of the diastereomeric carbamates formed by reaction
of (R)- and (S)-NNAL with (R)-(+)-MBIC were thereby assigned. Conversion of
metabolically produced NNAL to the same carbamates allowed us to assign the
NNAL formed from NNK by rat liver microsomes as (R)-NNAL. The major and
minor NNAL-glucuronide diastereomers found in the urine of patas monkeys
and humans exposed to NNK were similarly assigned; they were formed from
(R)-NNAL and (S)- NNAL, respectively.
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