Characterization of enzymes participating in carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human placenta

dr-Methylnitrosamino 1-(3-pyridyl)-1-butanone (NNK) has been identified as one of the strongest nitrosamine carcinogens in tobacco products in all spe cies tested. Carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)-1-buta nol (NNAL) followed by glucuronosylation is considered to be the main detox ification pathway in humans. In previous investigations, we have identified a microsomal NNK carbonyl reductase as being identical to 11 beta -hydroxy steroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductas e (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, AKR 1C2 and AKR1C4 from the aldo-keto reductase (AKR) superfamily were demonstr ated to be responsible for NNK reduction. Since NNK and/or its metabolites can diffuse through the placenta and reach fetal tissues, we now investigat ed NNK carbonyl reduction in the cytosolic fraction of human placenta in ad dition to that in microsomes. Concluding from the sensitivity to menadione, ethacrynic acid, rutin and quercitrin as specific inhibitors, mainly carbo nyl reductase (EC 1.1.1.184) seems to perform this reaction in human placen ta cytosol. The presence of carbonyl reductase was confirmed by RT-PCR. Thi s is the first report to provide evidence that NNAL formation in placenta i s mediated by carbonyl reductase. (C) 2001 Elsevier Science Ireland Ltd. Al l rights reserved.