Interindividuelle Unterschiede in der Aktivität und Expression der Nitrosaminketon reduzierenden Enzyme 11beta-Hydroxysteroid-Dehydrogenase Typ 1 und Carbonylreduktase in der menschlichen Lunge
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Philipps-Universität Marburg
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Abstract
The tobacco specific nitrosamine
4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), which is
found in tobacco products and tobaco smoke, plays obviously an
important role in the lung cancer induction in smokers. NNK
requires metabolic activation by cytochrome P450 mediated
alpha-hydroxylation to exhibit its carcinogenic properties by
elektrophile metabolites and DNA alkylation. On the other hand,
NNK is inactivated by carbonyl reduction to its
alcohol-equivalent 4-methylnitrosamino-1-(3-pyridyl)-1-butanol
(NNAL) followed by glucuronidation and final excretion into
urine or bile. Microsomal 11beta-hydroxysteroid dehydrogenase
type 1 (11beta-HSD 1) (EC 1.1.1.146) and cytosolic carbonyl
reductase (CR) (EC 1.1.1.184) have been shown to be mainly
responsible for NNAL formation in liver and lung. They are
subject of this study to show possible differences in the
individual susceptibility of tobacco-smoke related lung cancer.
Comparative investigations of human lung tissue samples from 17
patients were performed with respect to the expression and
activity of 11beta-HSD 1 and carbonyl reductase. Varying levels
in 11beta-HSD 1 and carbonyl reductase expression could be
found in these patients, as revealed by RT-PCR (mRNA amounts)
and ELISA (11beta-HSD 1 protein amounts in microsomes).
Furthermore, the tissue samples showed a different activity and
inhibitor profile for both enzymes (measured by chromatography
of NNAL after tissue incubation with NNK). The different
parameters for the patients are lacking correlations among each
other. The variations in the expression and activity of NNK
carbonyl reducing enzymes may constitute a determinant in the
interindividually different NNK detoxification capacity and
thus may be linked to the differences observed in the
individual susceptibility of tobacco-smoke related lung cancer.
Endogenous and exogenous factors, enzyme polymorphisms and for
example so far unkown NNK reducing enzymes can play a
role.
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Dates
Created: 2004Issued: 2004-05-19Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Lung cancer , 4-Methylnitrosamino-1-(3-pyridyl)-1-butanoneBronchialkarzinom , 4-Methylnitrosamino-1-(3-pyridyl)-1-butanon11beta-Hydroxysteroid dehydrogenase type 1 , 11betNNKNNK , Carbonylreduktase11beta-Hydroxysteroid-Dehydrogenase Typ 1 , 11Carbonyl reductase
DFG-subjects
CarbonylreduktionNitrosamineEnzymRauchenELISAReduktasenLungenkrebsEnzymaktivität , EnzyminhibitorTabakkonsumPCR
DDC-Numbers
610
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Finckh, Clemens: Interindividuelle Unterschiede in der Aktivität und Expression der Nitrosaminketon reduzierenden Enzyme 11beta-Hydroxysteroid-Dehydrogenase Typ 1 und Carbonylreduktase in der menschlichen Lunge. : Philipps-Universität Marburg 2004-05-19. DOI: https://doi.org/10.17192/z2004.0282.
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This item has been published with the following license: In Copyright