Carcinogenesis, Vol. 22, No. 1, 107-114,
January 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
Human cervical tissue metabolizes the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, via 
-hydroxylation and carbonyl reduction pathways
American Health Foundation, Valhalla, NY 10595 and
1 Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
We determined the ability of human epithelial cervical cells, human cervical microsomes and cytosol to metabolize 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). All preparations metabolized NNK by 
-hydroxylation, demonstrated by the presence of 4-oxo-4-(3-pyridyl)butyric acid (keto acid), and by carbonyl reduction, illustrated by the formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Cervical cells metabolized NNK by the oxidative pathway to an extent comparable to that by the reductive pathway. In both human cervical cytosol and microsomes, the concentration of -hydroxylation products ranged from undetectable to 10 times lower than those of NNAL. An apparent Km and Vmax of 7075 µM and 650 pmol/mg/min, respectively, were determined for the keto acid in one microsomal preparation. NNAL was formed in all preparations at the highest levels, ranging from 16.9 to 35.5 pmol/106 cells in incubations with ectocervical cells and 6.2 pmol/106 cells in incubations with endocervical cells. NNAL levels were 1.88–4.95 and 1.44–2.08 pmol/mg/min in human cervical microsomes and cytosolic fractions, respectively. An apparent Km of 739 µM and a Vmax of 1395 pmol/mg/min for NNAL formation were established in the same microsomal preparation used for the keto acid kinetics study. The stereochemistry of the NNAL formed in incubations of NNK with human cervical cells and subcellular fractions was determined by derivatization with (S)-(–)-methylbenzyl isocyanate. Human cervical cells and microsomes both formed the (R)-enantiomer of NNAL almost exclusively; incubations with human cervical cytosol resulted predominantly in the formation of the (S)-enantiomer. Substrates for 11ß-hydroxysteroid dehydrogenase, cortisone, glycyrrhizic acid and metyrapone all inhibited the formation of NNAL in incubations with human cervical microsomes; the inhibition ranged from 16% to 80%. These studies illustrate that human cervical tissue can metabolize NNK by both oxidative and reductive pathways and that 11ß-HSD may, in part, be responsible for the carbonyl reduction of NNK.
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