Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Langenbeck's Archives of Surgery Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

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

References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130

    Article  PubMed  Google Scholar 

  2. Gallicchio L, Kouzis A, Genkinger JM, Burke AE, Hoffman SC, Diener-West M, Helzlsouer KJ, Comstock GW, Alberg AJ (2006) Active cigarette smoking, household passive smoke exposure, and the risk of developing pancreatic cancer. Prev Med 42:200–205

    Article  PubMed  Google Scholar 

  3. Shen M, Boffetta P, Olsen JH, Andersen A, Hemminki K, Pukkala E, Tracey E, Brewster DH, McBride ML, Pompe-Kirn V, Kliewer EV, Tonita JM, Chia KS, Martos C, Jonasson JG, Colin D, Scelo G, Brennan P (2006) A pooled analysis of second primary pancreatic cancer. Am J Epidemiol 163:502–511

    Article  PubMed  Google Scholar 

  4. Chiu BCH, Lynch CF, Cerhan JR, Cantor KP (2001) Cigarette smoking and risk of bladder, pancreas, kidney, and colorectal cancers in Iowa. Ann Epidemiol 11:28–37

    Article  PubMed  CAS  Google Scholar 

  5. Coughlin SS, Calle EE, Patel AV, Thun MJ (2000) Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control 11:915–923

    Article  PubMed  CAS  Google Scholar 

  6. Wynder EL, Mabuchi K, Maruchi N, Fortner JG (1973) A case control study of cancer of the pancreas. Cancer 31:641–648

    Article  PubMed  CAS  Google Scholar 

  7. Muscat JE, Stellman SD, Hoffmann D, Wynder EL (1997) Smoking and pancreatic cancer in men and women. Cancer Epidemiol Biomark Prev 6:15–19

    CAS  Google Scholar 

  8. Ghadirian P, Simard A, Baillargeon J (1991) Tobacco, alcohol, and coffee and cancer of the pancreas. A population-based, case control study in Quebec, Canada. Cancer 67:2664–2670

    Article  PubMed  CAS  Google Scholar 

  9. Kahn HA (1966) The Dorn study of smoking and mortality among U.S. veterans: report on eight and one-half years of observation. Natl Cancer Inst Monogr 19:1–125

    PubMed  CAS  Google Scholar 

  10. Hoffmann D, Hoffmann I, El-Bayoumy K (2001) The less harmful cigarette: a controversial issue. A tribute to Ernst L. Wynder. Chem Res Toxicol 14:767–790

    Article  PubMed  CAS  Google Scholar 

  11. Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11:559–603

    Article  PubMed  CAS  Google Scholar 

  12. Hoffmann D, Rivenson A, Abbi R, Wynder EL (1993) A study of tobacco carcinogenesis: effect of the fat content of the diet on the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats. Cancer Res 53:2758–2761

    PubMed  CAS  Google Scholar 

  13. Rivenson A, Hoffmann D, Prokopczyk B, Amin S, Hecht SS (1988) Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and Areca-derived N-nitrosamines. Cancer Res 48:6912–6917

    PubMed  CAS  Google Scholar 

  14. Ouyang H, Mou L-j, Luk C, Liu N, Karaskova J, Squire J, Tsao M-S (2000) Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype. Am J Pathol 157:1623–1631

    PubMed  CAS  Google Scholar 

  15. Prokopczyk B, Hoffmann D, Bologna M, Cunningham AJ, Trushin N, Akerkar S, Boyiri T, Amin S, Desai D, Colosimo S, Pittman B, Leder G, Ramadani M, Henne-Bruns D, Beger HG, El-Bayoumy K (2002) Identification of tobacco-derived compounds in human pancreatic juice. Chem Res Toxicol 15:677–685

    Article  PubMed  CAS  Google Scholar 

  16. Hecht SS, Carmella SG, Murphy SE, Akerkar S, Brunnemann K, Hoffmann D (1993) A tobacco-specific lung carcinogen in the urine of men exposed to cigarette smoke. N Engl J Med 329:1543–1546

    Article  PubMed  CAS  Google Scholar 

  17. Carmella SG, Akerkar SA, Richie JP, Hecht SS (1995) Intraindividual and interindividual differences in metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokers’ urine. Cancer Epidemiol Biomark Prev 4:635–642

    CAS  Google Scholar 

  18. Upadhyaya P, Kenney PMJ, Hochalter JB, Wang M, Hecht SS (1999) Tumorigenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol enantiomers and metabolites in the A/J mouse. Carcinogenesis 20:1577–1582

    Article  PubMed  CAS  Google Scholar 

  19. Staretz ME, Murphy SE, Patten CJ, Nunes MG, Koehl W, Amin S, Koenig LA, Guengerich FP, Hecht SS (1997) Comparative metabolism of the tobacco-related carcinogens benzo[a]pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and N′-nitrosonornicotine in human hepatic microsomes. Drug Metab Dispos 25:154–162

    PubMed  CAS  Google Scholar 

  20. Chen CB, Hecht SS, Hoffmann D (1978) Metabolic α-hydroxylation of the tobacco-specific carcinogen, N′-nitrosonornicotine. Cancer Res 38:3639–3645

    PubMed  CAS  Google Scholar 

  21. McKennis H, Schwartz SL, Turnbull LB, Tamaki E, Bowman ER (1964) Metabolic formation of gamma-(3-pyridyl)-gamma-hydroxybutyric acid and its possible intermediary role in mammalian metabolism of nicotine. J Biol Chem 239:3981–3989

    PubMed  CAS  Google Scholar 

  22. Prokopczyk B, Trushin N, Leszczynska J, Waggoner SE, El-Bayoumy K (2001) Human cervical tissue metabolizes the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, via α-hydroxylation and carbonyl reduction pathways. Carcinogenesis 22:107–114

    Article  PubMed  CAS  Google Scholar 

  23. Smith TJ, Stoner GD, Yang CS (1995) Activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human lung microsomes by cytochromes P450, lipoxygenase, and hydroperoxides. Cancer Res 55:5566–5573

    PubMed  CAS  Google Scholar 

  24. Hecht SS, Spratt TE, Trushin N (1997) Absolute configuration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol formed metabolically from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 18:1851–1854

    Article  PubMed  CAS  Google Scholar 

  25. Hecht SS, Spratt TE, Trushin N (2000) Corrigendum: Absolute configuration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol formed metabolically from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 20:850

    Google Scholar 

  26. Maser E (1998) 11β-Hydroxysteroid dehydrogenase responsible for carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes. Cancer Res 58:2996–2303

    PubMed  CAS  Google Scholar 

  27. Zimmerman CL, Wu Z, Upadhyaya P, Hecht SS (2004) Stereoselective metabolism and tissue retention in rats of the individual enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), metabolites of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Carcinogenesis 25:1237–1242

    Article  PubMed  CAS  Google Scholar 

  28. Lao YB, Yu NX, Kassie F, Villalta PW, Hecht SS (2007) Formation and accumulation of pyridyloxobutyl DNA adducts in F344 rats chronically treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Chem Res Toxicol 20:235–245

    Article  CAS  Google Scholar 

  29. Soldan M, Nagel G, Losekam M, Ernst M, Maser E (1999) Interindividual variability in the expression and NNK carbonyl reductase activity of 11β-hydroxysteroid dehydrogenase 1 in human lung. Cancer Lett 145:49–56

    Article  PubMed  CAS  Google Scholar 

  30. Anderson KE, Hammons GJ, Kadlubar FF, Potter JD, Kaderlik KR, Ilett KF, Minchin RF, Teitel CH, Chou HC, Martin MV, Guengerich FP, Barone GW, Lang NP, Peterson LA (1997) Metabolic activation of aromatic amines by human pancreas. Carcinogenesis 18:1085–1092

    Article  PubMed  CAS  Google Scholar 

  31. Prokopczyk B, Leder G, Trushin N, Cunningham AJ, Akerkar S, Pittman B, Ramadani M, Straeter J, Beger HG, Henne-Bruns D, El-Bayoumy K (2005) 4-Hydroxy-1-(3-pyridyl)-1-butanone, an indicator for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA damage, is not detected in human pancreatic tissue. Cancer Epidemiol Biomark Prev 14:540–541

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Penn State College of Medicine, P.O. Box 850, H072, Hershey, PA, 17033-0850, USA

    Neil Trushin

  2. Department of Visceral and Transplantation Surgery, University of Ulm, Ulm, Germany

    Gerhard Leder, Doris Henne-Bruns & Marco Ramadani

  3. Penn State Cancer Institute, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Karam El-Bayoumy & Bogdan Prokopczyk

  4. Institute for Cancer Prevention, Valhalla, NY, 10595, USA

    Dietrich Hoffmann

  5. Center of Oncologic, Endocrine and Minimal Invasive Surgery, Donauklinik, Neu-Ulm, Germany

    Hans G. Beger

Authors
  1. Neil Trushin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerhard Leder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karam El-Bayoumy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dietrich Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans G. Beger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Doris Henne-Bruns
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marco Ramadani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bogdan Prokopczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neil Trushin.

Additional information

Neil Trushin and Gerhard Leder equally contributed to this work.

This work was supported by Public Health Service grant CA76228 from the National Cancer Institute, National Institute of Health, Department of Health and Human Services.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trushin, N., Leder, G., El-Bayoumy, K. et al. The tobacco carcinogen NNK is stereoselectively reduced by human pancreatic microsomes and cytosols. Langenbecks Arch Surg 393, 571–579 (2008). https://doi.org/10.1007/s00423-007-0265-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-007-0265-3

Keywords

Search

Navigation