Different inhibitory potential of sex hormones on NNK detoxification in vitro: A possible explanation for gender-specific lung cancer risk

Smoking women are probably at a higher risk to develop lung cancer than men. Different explanations exist for these findings, a gender-specific impairment of tobacco carcinogen metabolism being one of them. In this study, we examined the inhibition of NNK reduction to NNAL, the first and most import...

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Bibliographic Details
Published in:Cancer letters 2017-10, Vol.405, p.120-126
Main Authors: Stapelfeld, Claudia, Neumann, Karolina-Theresa, Maser, Edmund
Format: Article
Language:English
Subjects:
17β-Estradiol
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
Carbonyl reduction
Carcinogens
Carcinogens - metabolism
Contraception
Contraceptives
Detoxification
Enzymes
Ethinylestradiol
Female
Gender
Gonadal Steroid Hormones - pharmacology
Health risk assessment
Health risks
Hormone replacement therapy
Humans
Inhibition
Inhibitors
Liver - drug effects
Lung cancer
Lung Neoplasms - metabolism
Lungs
Male
Metabolism
Nitrosamines - metabolism
Pregnancy
Progesterone
Pyridines - metabolism
Reductases
Risk groups
Sex
Sex Factors
Sex hormones
Sexes
Smoking
Smoking - adverse effects
Testosterone
Tobacco
Tobacco Products
Tumor Cells, Cultured
Womens health
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Summary:Smoking women are probably at a higher risk to develop lung cancer than men. Different explanations exist for these findings, a gender-specific impairment of tobacco carcinogen metabolism being one of them. In this study, we examined the inhibition of NNK reduction to NNAL, the first and most important detoxication step of this tobacco-specific carcinogen. It is mediated by different carbonyl reductases of the SDR (CBR1 and 11βHSD1) and AKR (AKR1B10, AKR1C1, AKR1C2 and AKR1C4) superfamilies. Inhibition constants of NNK reduction were determined with male (testosterone) and female (estradiol, progesterone) sex hormones and the contraceptives ethinylestradiol and drospirenone in A549 cells and with purified enzymes. Female sex hormones turned out to be stronger inhibitors than testosterone. The gestagen progesterone and its synthetic derivative drospirenone are the strongest inhibitors with Ki-values similar to hormone levels in pregnant women or women using hormonal contraceptives. Therefore, pregnancy or hormonal contraception may commit these women as high risk groups. The results of this study support the hypothesis that women bear a higher lung cancer risk when smoking because of female sex hormones acting as inhibitors of NNK detoxication.
ISSN:0304-3835
1872-7980
1872-7980
DOI:10.1016/j.canlet.2017.07.016