Langenbeck's Archives of Surgery

, Volume 393, Issue 4, pp 571–579 | Cite as

The tobacco carcinogen NNK is stereoselectively reduced by human pancreatic microsomes and cytosols

  • Neil Trushin
  • Gerhard Leder
  • Karam El-Bayoumy
  • Dietrich Hoffmann
  • Hans G. Beger
  • Doris Henne-Bruns
  • Marco Ramadani
  • Bogdan Prokopczyk
Original Article
First Online:
Received:
Accepted:

Abstract

Background/aims

Cigarette smoking increases the risk of cancer of the pancreas. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the only known environmental compound that induces pancreatic cancer in laboratory animals. Concentrations of NNK are significantly higher in the pancreatic juice of smokers than in that of nonsmokers. The chiral NNK metabolite, (R,S)-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is itself a potent pancreatic carcinogen in rats. The carcinogenicity of NNAL is related to its stereochemistry; (S)-NNAL is a more potent lung tumorigen in the A/J mouse than is (R)-NNAL. In this study, we determined the potential of the human pancreas to convert NNK into NNAL.

Materials and methods

Human pancreatic microsomes and cytosols were incubated with [5-3H]NNK, and the metabolic products were determined by high-performance liquid chromatography (HPLC).

Results

(S)-NNAL was the predominant isomer formed in all cytosolic incubations. In ten microsomal samples, NNAL was formed at an average rate of 3.8 ± 1.6 pmol/mg/min; (R)-NNAL was the predominant isomer in this group. The average rate of NNAL formation in 18 other microsomal samples was significantly lower, 0.13 ± 0.12 pmol/mg/min (p < 0.001); (S)-NNAL was the predominant isomer formed in this group.

Conclusion

In human pancreatic tissues, there is intraindividual variability regarding the capacity for, and stereoselectivity of, carbonyl reduction of NNK.

Keywords

NNK NNAL Pancreatic cancer Smoking 

Abbreviations

11β-HSD

11β-hydroxysteroid dehydrogenase

DTT

dithiothreitol

GA

glycyrrhizic acid

keto acid

4-oxo-4-(3-pyridyl)-1-butanoic acid

keto alcohol (HPB)

4-hydroxy-4-(3-pyridyl)-1-butanone

(S)-MBIC

(S)-(−)-(α)-methylbenzyl isocyanate

NNAL

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol

NNAL-Gluc

[4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-β-O-d-glucosiduronic acid

NNAL-MBIC

[4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl] N-(α-methylbenzyl) carbamate

NNK

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

PMSF

phenylmethylsulfonyl fluoride

TSNA

tobacco-specific nitrosamines

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Neil Trushin
    • 1
  • Gerhard Leder
    • 2
  • Karam El-Bayoumy
    • 3
  • Dietrich Hoffmann
    • 4
  • Hans G. Beger
    • 5
  • Doris Henne-Bruns
    • 2
  • Marco Ramadani
    • 2
  • Bogdan Prokopczyk
    • 3
  1. 1.Department of PharmacologyPenn State College of MedicineHersheyUSA
  2. 2.Department of Visceral and Transplantation SurgeryUniversity of UlmUlmGermany
  3. 3.Penn State Cancer InstitutePenn State College of MedicineHersheyUSA
  4. 4.Institute for Cancer PreventionValhallaUSA
  5. 5.Center of Oncologic, Endocrine and Minimal Invasive SurgeryDonauklinikNeu-UlmGermany

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