The profile of urinary metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats is determined by its pulmonary metabolism

• Verfasst von: Schneider, Thomas [VerfasserIn]
• Verfasst von: Frei, Eva [VerfasserIn]
• Verfasst von: Wießler, Manfred [VerfasserIn]
• Titel: The profile of urinary metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats is determined by its pulmonary metabolism
• Verf.angabe: Thomas Schneider, Eva Frei, Manfred Wiessler
• E-Jahr: 1999
• Jahr: 22 April 1999
• Umfang: 20 S.
• Fussnoten: Gesehen am 04.02.2019
• Titel Quelle: Enthalten in: Chemico-biological interactions
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1969
• Jahr Quelle: 1999
• Band/Heft Quelle: 118(1999), 3, Seite 247-266
• ISSN Quelle: 1872-7786
• DOI: doi:10.1016/S0009-2797(99)00083-6
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Acetone
• Sach-SW: Glucuronide
• Sach-SW: Hepatocytes
• Sach-SW: Nicotine
• Sach-SW: NNAL
• Sach-SW: NNK
• Sach-SW: Phenethyl isothiocyanate
• Sach-SW: Phenobarbital
• Sach-SW: Primary lung cells
• K10plus-PPN: 1587221934

Abstract

Metabolism of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats was compared to metabolism in primary lung and liver cells. Untreated rats and rats pretreated with phenobarbital, acetone or phenethyl isothiocyanate (PEITC) were used for all experiments. Also the influence of [-]-1-methyl-2-[3-pyridyl]-pyrrolidine (nicotine) administered concomitantly with NNK, or incubated with isolated cells, upon NNK metabolism was investigated and found to be only marginal upon α-hydroxylation and pyridine N-oxidation in vivo. In hepatocytes nicotine inhibited NNK pyridine N-oxidation, α-hydroxylation and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), whereas in lung cells the influence of nicotine was not as pronounced. In vivo phenobarbital induced α-hydroxylation and pyridine N-oxidation. In vitro the effects of the modulators were most pronounced upon hepatocytes, where phenobarbital greatly induced pyridine N-oxidation and PEITC inhibited α-hydroxylation. NNAL was conjugated to its β-glucuronide in lung cells at four times higher rates than in hepatocytes. The ratios of the sum of N-oxides to the sum of α-hydroxylation products in vivo were similar to those in lung cells, especially at low NNK concentrations (1 μM), while in hepatocytes α-hydroxylation was more pronounced. The same correlation of metabolism in isolated lung cells with whole rats was observed if oxidative NNAL metabolism was related to oxidative NNK metabolism. Here hepatocytes showed a much higher formation of NNAL oxidation products than either lung cells formed, or rats excreted in urine. This was true despite a lower rate of metabolism in the lung than in liver if based on cell number, the rate based on mg protein was four times higher in lung than liver. Only after phenobarbital treatment was the contribution of hepatic metabolism to excreted metabolites important. In conclusion the lung which is also the target of NNK carcinogenesis, and not the liver, is the organ with the most important contribution to NNK and NNAL metabolism at concentrations relevant to human exposure.