Characterization of enzymes participating in carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human placenta |
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| Institution: | 1. Shandong Key Laboratory of Oil and Gas Storage and Transport Safety Engineering, College of Pipeline and Civil Engineering, China University of Petroleum, Qingdao 266580, China;2. Key Laboratory of Biomass Gasification Technology of Shandong, Energy Research Institute of Shandong Academy of Sciences, Jinan 250014, China;1. Department of Chemistry, Faculty of Science, Dicle University, 21280 Diyarbak?r, Turkey;2. Science and Technology Application and Research Center (SIUBTAM), Siirt University, 56000 Siirt, Turkey;1. State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Rd 2, Haidian District, 100193 Beijing, China;3. Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Rd 2, Haidian District, 100193 Beijing, China;1. Department of Electrical and Computer Engineering, College of Engineering & Sciences, Purdue University Northwest, Hammond, IN 46323, USA;2. Department of Computer Science & Engineering, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram, AP 522502, India;3. Department of Applied Computing, College of Computing, Michigan Technological University, Houghton, MI 49931, USA;1. Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China;2. National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, and National Technology Innovation Center for Synthetic Biology, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China |
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| Abstract: | 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) has been identified as one of the strongest nitrosamine carcinogens in tobacco products in all species tested. Carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. In previous investigations, we have identified a microsomal NNK carbonyl reductase as being identical to 11ß-hydroxysteroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Recently, we provided evidence that carbonyl reduction of NNK does also take place in cytosol from mouse and human liver and lung. In human liver cytosol, carbonyl reductase, a SDR enzyme, and AKR1C1, AKR1C2 and AKR1C4 from the aldo-keto reductase (AKR) superfamily were demonstrated to be responsible for NNK reduction. Since NNK and/or its metabolites can diffuse through the placenta and reach fetal tissues, we now investigated NNK carbonyl reduction in the cytosolic fraction of human placenta in addition to that in microsomes. Concluding from the sensitivity to menadione, ethacrynic acid, rutin and quercitrin as specific inhibitors, mainly carbonyl reductase (EC 1.1.1.184) seems to perform this reaction in human placenta cytosol. The presence of carbonyl reductase was confirmed by RT-PCR. This is the first report to provide evidence that NNAL formation in placenta is mediated by carbonyl reductase. |
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