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ENANTIOSELECTIVITY OF CARBONYL REDUCTION OF 4-METHYLNITROSAMINO-1-(3-PYRIDYL)-1-BUTANONE BY TISSUE FRACTIONS FROM HUMAN AND RAT AND BY ENZYMES ISOLATED FROM HUMAN LIVER

Department of Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany

Detoxication of the tobacco-specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in humans is mainly due to carbonyl reduction to the chiral alcohol 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL), which undergoes glucuronidation and excretion. NNAL has a carcinogenic potential with (S)-NNAL being more tumorigenic in the mouse. Therefore, the enantioselectivity of NNK reductases seems toxicologically relevant. NNAL enantiomers were measured by a novel high-performance liquid chromatography procedure. The aldo-keto reductases AKR1C1, 1C2, and 1C4 and carbonyl reductase purified from human liver cytosol produced NNAL with >90% (S)-enantiomer in accordance with the enantioselectivity of NNK reduction by cytosol from liver, placenta, and lung. In contrast, the (R)-NNAL content was 35% on NNK reduction with 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) purified from human liver microsomes, but around 70% with human microsomes. The selectivity for (R)-NNAL formation was still higher with microsomes from placenta (87%) and lung (89% in 10 of 11 surgical samples). Microsomes from lung of one patient reduced NNK at a much lower rate, with production of 14% (R)-NNAL. This points to predominant reduction in microsomes by an enzyme with selectivity for (R)-NNAL formation that was apparently absent from the lung of one patient. Experiments with 18ß-glycyrrhetinic acid, a potent inhibitor of 11ß-HSD1, also indicated a minor or no role for 11ß-HSD1. Rat liver and lung microsomes produced NNAL with about 33% and 55% (R)-enantiomer and a mean contribution of 11ß-HSD1 of 12% and 32%, respectively. Multiple enzymes seem to participate in NNK reduction in human and rat tissues.

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				P. J. Brown, L. L. Bedard, K. R. Reid, D. Petsikas, and T. E. Massey Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes Drug Metab. Dispos., November 1, 2007; 35(11): 2086 - 2094. [Abstract] [Full Text] [PDF]

				H.-J. Martin, U. Breyer-Pfaff, V. Wsol, S. Venz, S. Block, and E. Maser PURIFICATION AND CHARACTERIZATION OF AKR1B10 FROM HUMAN LIVER: ROLE IN CARBONYL REDUCTION OF XENOBIOTICS Drug Metab. Dispos., March 1, 2006; 34(3): 464 - 470. [Abstract] [Full Text] [PDF]