Characterization of enzymes responsible for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) detoxification pathway in lungs of Chinese population: Carbonyl reduction and glucuronidation

Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent carcinogens found in mainstream and sidestream smoke and considered to be a causative agent for lung cancer in active and passive smokers. Carbonyl reduction followed by glucuronidation is considered to be the main detoxification pathway of NNK. Microsomal 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD 1) and cytosolic carbonyl reductase (CR) are responsible for NNK carbonyl reduction, and UDP-glucuronosyltransferase 1A4 (UGT1A4) and UDP-glucuronosyltransferase 2B7 (UGT2B7) catalyze 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) glucuronidation. To better characterize this pathway, the expression and kinetics of 11β-HSD 1 and CR, as well as the expression of UGT1A4 and UGT2B7, was investigated in lungs of Chinese people. Kinetic studies for 11β-HSD 1 and CR showed that there was large inter-individual variability in the capacity for NNK carbonyl reduction. Compared with cytosol, there was increased catalytic efficiency for NNAL formation in microsomes. The higher activities of both 11β-HSD 1 and CR were observed in lung tissues of males than females. UGT1A4 and UGT2B7 mRNA were detected in lungs from a variety of different patients and wide inter-individual variations were observed. These observations should be useful in improving the risk estimates and prevention of lung cancer for the Chinese population exposed to tobacco smoke.