PT  - JOURNAL ARTICLE
AU  - Ursula Breyer-Pfaff
AU  - Hans-Jörg Martin
AU  - Michael Ernst
AU  - Edmund Maser
TI  - 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
DP  - 2004 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 915--922
VI  - 32
IP  - 9
4099  - http://dmd.aspetjournals.org/content/32/9/915.short
4100  - http://dmd.aspetjournals.org/content/32/9/915.full
SO  - Drug Metab Dispos2004 Sep 01; 32
AB  - 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 11β-hydroxysteroid dehydrogenase type 1 (11β-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 18β-glycyrrhetinic acid, a potent inhibitor of 11β-HSD1, also indicated a minor or no role for 11β-HSD1. Rat liver and lung microsomes produced NNAL with about 33% and 55% (R)-enantiomer and a mean contribution of 11β-HSD1 of 12% and 32%, respectively. Multiple enzymes seem to participate in NNK reduction in human and rat tissues. The American Society for Pharmacology and Experimental Therapeutics