title: Sex hormones reduce NNK detoxification through inhibition of short-chain dehydrogenases/reductases and aldo-keto reductases in vitro.
abstract: Carbonyl reduction is an important metabolic pathway for endogenous and xenobiotic substances. The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine ketone) is classified as carcinogenic to humans (IARC, Group 1) and considered to play the most important role in tobacco-related lung carcinogenesis. Detoxification of NNK through carbonyl reduction is catalyzed by members of the AKR- and the SDR-superfamilies which include AKR1B10, AKR1C1, AKR1C2, AKR1C4, 11β-HSD1 and CBR1. Because some reductases are also involved in steroid metabolism, five different hormones were tested for their inhibitory effect on NNK carbonyl reduction. Two of those hormones were estrogens (estradiol and ethinylestradiol), another two hormones belong to the gestagen group (progesterone and drospirenone) and the last tested hormone was an androgen (testosterone). Furthermore, one of the estrogens (ethinylestradiol) and one of the gestagens (drospirenone) are synthetic hormones, used as hormonal contraceptives. Five of six NNK reducing enzymes (AKR1B10, AKR1C1, AKR1C2, AKR1C4 and 11β-HSD1) were significantly inhibited by the tested sex hormones. Only NNK reduction catalyzed by CBR1 was not significantly impaired. In the case of the other five reductases, gestagens had remarkably stronger inhibitory effects at a concentration of 25 μM (progesterone: 66-88% inhibition; drospirenone: 26-87% inhibition) in comparison to estrogens (estradiol: 17-51% inhibition; ethinylestradiol: 14-79% inhibition) and androgens (14-78% inhibition). Moreover, in most cases the synthetic hormones showed a greater ability to inhibit NNK reduction than the physiologic derivatives. These results demonstrate that male and female sex hormones have different inhibitory potentials, thus indicating that there is a varying detoxification capacity of NNK in men and women which could result in a different risk for developing lung cancer.
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105 Kiel, Germany. Electronic address: stapelfeld@toxi.uni-kiel.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stapelfeld
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105 Kiel, Germany.
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
mesh_terms: D000074408:Aldo-Keto Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000736:Androstenes / Q000737:chemistry / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D042341:Gonadal Hormones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology; D009602:Nitrosamines / Q000737:chemistry / Q000378:metabolism*; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D000074583:Short Chain Dehydrogenase-Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014026:Nicotiana / Q000737:chemistry / Q000378:metabolism
chemical_list: D000736:Androstenes; D002273:Carcinogens; D042341:Gonadal Hormones; D009602:Nitrosamines; D011994:Recombinant Proteins; D011374:Progesterone; D004958:Estradiol; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000074408:Aldo-Keto Reductases; D000074583:Short Chain Dehydrogenase-Reductases; C035144:drospirenone
keywords: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); Aldo-keto reductases (AKR); Carbonyl reduction; Enzyme inhibition; Sex hormones; Short-chain dehydrogenases/reductases (SDR)