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

• Published in: Toxicological and environmental chemistry Vol. 91; no. 2; pp. 375 - 387
• Main Authors: Liu, Y.-H., Zhang, F., Ao, Y., Dan, H., Peng, R.-X.
• Format: Journal Article
• Language: English
• Published: Taylor & Francis Group 01.03.2009
• Subjects: carbonyl reduction; detoxification; glucuronidation; lung; NNK
• ISSN: 0277-2248; 1029-0486
• DOI: 10.1080/02772240802188064

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.