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.
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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 18beta-glycyrrhetinic acid, a potent inhibitor of 11beta-HSD1, also indicated a minor or no role for 11beta-HSD1. Rat liver and lung microsomes produced NNAL with about 33% and 55% (R)-enantiomer and a mean contribution of 11beta-HSD1 of 12% and 32%, respectively. Multiple enzymes seem to participate in NNK reduction in human and rat tissues.
Department of Pharmacology and Toxicology, University of Tübingen, Germany.
Ursula
U
Breyer-Pfaff
Hans-Jörg
HJ
Martin
Michael
M
Ernst
Edmund
E
Maser
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015089:20-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D000449:Aldehyde Reductase / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods / Q000639:trends; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology*; D009602:Nitrosamines / Q000737:chemistry / Q000378:metabolism*; D010088:Oxidoreductases / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D010920:Placenta / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D009602:Nitrosamines; D011725:Pyridines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D000449:Aldehyde Reductase; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol; D006034:Glycyrrhetinic Acid