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Research ArticleArticle

Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Primary Cultures of Rat Alveolar Type II Cells

Eberhard Schrader, Karen I. Hirsch-Ernst, Ekkehard Scholz, Georg F. Kahl and Heidi Foth
Drug Metabolism and Disposition February 2000, 28 (2) 180-185;
Eberhard Schrader
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Karen I. Hirsch-Ernst
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Ekkehard Scholz
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Georg F. Kahl
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Heidi Foth
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Abstract

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces primarily lung tumors, which are assumed to derive from malignant transformation of alveolar type II (AII) cells within the lung. To elicit its carcinogenic effects, NNK requires metabolic activation by cytochrome P-450 (CYP)-mediated α-hydroxylation. Therefore, in this study the metabolism of NNK and expression of the NNK-activating CYP isoform CYP2B1 were investigated in primary cultures of rat AII cells. Although basal expression of CYP2B1 decreased in a time-dependent manner during culture of AII cells, substantial CYP2B1 protein expression was observed in AII cell cultures after the first 24 h. When AII cells were incubated with 0.05 μM [5-3H]NNK,N-oxidation of NNK, which is thought to represent a detoxification pathway, was predominant (42%). α-Hydroxylated metabolites resulting from metabolic activation of NNK amounted to 35% of all detected metabolites. However, the proportion of α-hydroxylated metabolites decreased to 17% of all detected metabolites when AII cells were incubated with a 100-fold higher concentration of NNK (5 μM). In summary, this study indicates a remarkable activity of cultured AII cells to metabolize NNK, leading to substantial metabolic activation of NNK, which was more pronounced in incubations at low NNK concentration. Because exposure to NNK via cigarette smoking is thought to lead to very low plasma NNK concentrations (1–15 pM), these data suggest that metabolic activation of NNK in cigarette smokers might occur to a larger extent than would be expected according to previous metabolic studies performed with high (micromolar) NNK concentrations.

Footnotes

  • Send reprint requests to: E. Schrader, Department of Toxicology, Institute of Pharmacology and Toxicology, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. E-mail:eschrade{at}med.uni-goettingen.de

  • This work was supported by the State of Saxony-Anhalt Grant no. LSA 2311A/0085 A.

  • Abbreviations used are::
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    AII
    alveolar type II
    CYP
    cytochrome P-450
    diol
    4-hydroxy-4-(3-pyridyl)-butanol
    NNAL
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    NNAL-Glu
    [4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-β-O-d-glycopyranosiduronic acid
    NNK-N-oxide
    4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone
    • Received July 12, 1999.
    • Accepted November 1, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
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Research ArticleArticle

Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Primary Cultures of Rat Alveolar Type II Cells

Eberhard Schrader, Karen I. Hirsch-Ernst, Ekkehard Scholz, Georg F. Kahl and Heidi Foth
Drug Metabolism and Disposition February 1, 2000, 28 (2) 180-185;

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Research ArticleArticle

Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Primary Cultures of Rat Alveolar Type II Cells

Eberhard Schrader, Karen I. Hirsch-Ernst, Ekkehard Scholz, Georg F. Kahl and Heidi Foth
Drug Metabolism and Disposition February 1, 2000, 28 (2) 180-185;
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