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Journal of Neuroimmune Pharmacology

, Volume 1, Issue 3, pp 317–322 | Cite as

Effects of Inhalant Nitrites on VEGF Expression: A Feasible Link to Kaposi's Sarcoma?

  • Ho-Leung FungEmail author
  • Doanh C. Tran
Invited Review

Abstract

Because inhalant nitrites (commonly known as “poppers”) were thought to be rapidly cleared from the body, the lay literature has somewhat downplayed their toxicity. However, scientific reports have documented their immunosuppressive effects in animals, and epidemiological studies have implicated their use with the development of Kaposi's sarcoma (KS) in humans. Because inhalant nitrites are exogenous nitric oxide donors, we hypothesized that these substances of abuse might exert part of their toxicological effects through this biochemical product, which has been shown to alter gene regulation and angiogenesis. In a series of studies, we showed that acute and chronic in vivo exposure to isobutyl nitrite (a representative inhalant nitrite) produced significant tissue-dependent alterations in the expression of a number of cancer- and angiogenesis-related genes in mice. In particular, hepatic mRNA and protein expression of vascular endothelial growth factor (VEGF) was significantly stimulated. The in vivo growth rate of a subcutaneous VEGF-responsive tumor was also shown to be accelerated by inhalant nitrite exposure. Because the development of KS is extensively linked to VEGF and its receptors, the purported link between inhalant nitrites and KS may be explained mechanistically, at least in part, through the stimulation of VEGF expression by these inhalants.

Key words

inhalant nitrite VEGF Kaposi's sarcoma mice pharmacokinetics microarray 

Notes

Acknowledgement

This study was funded in part by NIH grant DA15982. We thank Jessica Haas for technical assistance in the tumor study.

References

  1. Anon (1996a) Inhalant Abuse. NIDA Research Report Series, via http://www.nida.nih.gov, Research Reports/Inhalants/Inhalants4.html
  2. Anon (2003) Results from the 2002 National Survey on Drug Use and Health: National Findings. In: NHSDA Series H-22, DHHS Publication No. SMA 03-3836. Rockville, MD: Office of Applied Studies, Substance Abuse and Mental Health ServicesGoogle Scholar
  3. Archibald CP, Schechter MT, Craib KJ, Le TN, Douglas B, Willoughby B, O'Shaughnessy M (1990) Risk factors for Kaposi's sarcoma in the Vancouver Lymphadenopathy–AIDS Study. J Acquir Immune Defic Syndr 3:S18–S23PubMedGoogle Scholar
  4. Beral V, Bull D, Darby S, Weller I, Carne C, Beecham M, Jaffe H (1992) Risk of Kaposi's sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS [see comments]. Lancet 339:632–635PubMedCrossRefGoogle Scholar
  5. Brunton TL (1867) On the use of nitrite of amyl in angina pectoris. Lancet II:97–98Google Scholar
  6. Colfax GN, Mansergh G, Guzman R, Vittinghoff E, Marks G, Rader M, Buchbinder S (2001) Drug use and sexual risk behavior among gay and bisexual men who attend circuit parties: a venue-based comparison. J Acquir Immune Defic Syndr 28:373–379PubMedGoogle Scholar
  7. Cornali E, Zietz C, Benelli R, Weninger W, Masiello L, Breier G, Tschachler E, Albini A, Sturzl M (1996) Vascular endothelial growth factor regulates angiogenesis and vascular permeability in Kaposi's sarcoma. Am J Pathol 149:1851–1869PubMedGoogle Scholar
  8. Dulak J, Jozkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wojtowicz A, Szuba A, Cooke JP (2000) Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20:659–666PubMedGoogle Scholar
  9. Ford PW, Hamden KE, Whitman AG, McCubrey JA, Akula SM (2004) Vascular endothelial growth factor augments human herpesvirus-8 (HHV-8/KSHV) infection. Cancer Biol Ther 3:876–881PubMedCrossRefGoogle Scholar
  10. Goedert JJ, Biggar RJ, Melbye M, Mann DL, Wilson S, Gail MH, Grossman RJ, DiGioia RA, Sanchez WC, Weiss SH, et al. (1987) Effect of T4 count and cofactors on the incidence of AIDS in homosexual men infected with human immunodeficiency virus. JAMA 257:331–334PubMedCrossRefGoogle Scholar
  11. Jaffe HW, Choi K, Thomas PA, Haverkos HW, Auerbach DM, Guinan ME, Rogers MF, Spira TJ, Darrow WW, Kramer MA, Friedman SM, Monroe JM, Friedman-Kien AE, Laubenstein LJ, Marmor M, Safai B, Dritz SK, Crispi SJ, Fannin SL, Orkwis JP, Kelter A, Rushing WR, Thacker SB, Curran JW (1983) National case–control study of Kaposi's sarcoma and Pneumocystis carinii pneumonia in homosexual men: Part 1. Epidemiologic results. Ann Intern Med 99:145–151PubMedGoogle Scholar
  12. Kielbasa W, Fung HL (2000a) Pharmacokinetics of a model organic nitrite inhalant and its alcohol metabolite in rats. Drug Metab Dispos 28:386–391PubMedGoogle Scholar
  13. Kielbasa W, Fung HL (2000b) Nitrite inhalation in rats elevates tissue NOS III expression and alters tyrosine nitration and phosphorylation. Biochem Biophys Res Commun 275:335–342PubMedCrossRefGoogle Scholar
  14. Kielbasa WB, Bauer JA, Fung HL (1999) Analysis of isobutyl nitrite inhalant in rat and human blood: application for pharmacokinetic investigations. J Chromatogr B Biomed Sci Appl 734:83–89PubMedCrossRefGoogle Scholar
  15. Lange WR, Haertzen CA, Hickey JE, Snyder FR, Dax EM, Jaffe JH (1988) Nitrite inhalants: patterns of abuse in Baltimore and Washington, DC. Am J Drug Alcohol Abuse 14:29–39PubMedCrossRefGoogle Scholar
  16. Li AA, Thake DC, Kaempfe TA, Branch DK, O'Donnell P, Speck FL, Tyler TR, Faber WD, Jasti SL, Ouellette R, Banton MI (1999) Neurotoxicity evaluation of rats after subchronic inhalation exposure to isobutanol. Neurotoxicology 20:889–900PubMedGoogle Scholar
  17. Marchio S, Primo L, Pagano M, Palestro G, Albini A, Veikkola T, Cascone I, Alitalo K, Bussolino F (1999) Vascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi's sarcoma cells. J Biol Chem 274:27617–27622PubMedCrossRefGoogle Scholar
  18. Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS (1997) Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS–Kaposi sarcoma. Proc Natl Acad Sci USA 94:979–984PubMedCrossRefGoogle Scholar
  19. Mayer KH (1984) Inhalation-induced immunosuppression: sniffing out the volatile nitrite—AIDS connection editorial. Pharmacotherapy 4:235–236PubMedGoogle Scholar
  20. Mirvish SS, Haverkos HW (1987) Butyl nitrite in the induction of Kaposi's sarcoma in AIDS letter. N Engl J Med 317:1603PubMedGoogle Scholar
  21. Morgan MJ, Kimes AS, London ED (1992) Possible roles for nitric oxide in AIDS and associated pathology. Med Hypotheses 38:189–193PubMedCrossRefGoogle Scholar
  22. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22PubMedGoogle Scholar
  23. Newell GR, Mansell PW, Spitz MR, Reuben JM, Hersh EM (1985) Volatile nitrites. Use and adverse effects related to the current epidemic of the acquired immune deficiency syndrome. Am J Med 78:811–816PubMedCrossRefGoogle Scholar
  24. Partanen TA, Alitalo K, Miettinen M (1999) Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer 86:2406–2412PubMedCrossRefGoogle Scholar
  25. Sarvesvaran ER, Fysh R, Bowen DA (1992) Amyl nitrite related deaths. Med Sci Law 32:267–269PubMedGoogle Scholar
  26. Seo T, Park J, Choe J (2005) Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 1 inhibits transforming growth factor-beta signaling. Cancer Res 65:1738–1747PubMedCrossRefGoogle Scholar
  27. Soderberg LS (1994) T cell functions are impaired by inhaled isobutyl nitrite through a T- independent mechanism. Toxicol Lett 70:319–329PubMedCrossRefGoogle Scholar
  28. Soderberg LS (1998) Immunomodulation by nitrite inhalants may predispose abusers to AIDS and Kaposi's sarcoma. J Neuroimmunol 83:157–161PubMedCrossRefGoogle Scholar
  29. Soderberg LS (1999) Increased tumor growth in mice exposed to inhaled isobutyl nitrite. Toxicol Lett 104:35–41PubMedCrossRefGoogle Scholar
  30. Soderberg LS, Barnett JB (1993) Inhaled isobutyl nitrite compromises T-dependent, but not T-independent, antibody induction. Int J Immunopharmacol 15:821–827PubMedCrossRefGoogle Scholar
  31. Soderberg LS, Barnett JB (1995) Inhalation exposure to isobutyl nitrite inhibits macrophage tumoricidal activity and modulates inducible nitric oxide. J Leukoc Biol 57:135–140PubMedGoogle Scholar
  32. Soderberg LS, Flick JT, Barnett JB (1996) Leukopenia and altered hematopoietic activity in mice exposed to the abused inhalant, isobutyl nitrite. Exp Hematol 24:848–853.PubMedGoogle Scholar
  33. Tran DC (2004) in vivo angiogenic gene regulation by inhalant nitrite. Ph.D. thesis, Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, p 233Google Scholar
  34. Tran DC, Yeh KC, Brazeau DA, Fung HL (2003) Inhalant nitrite exposure alters mouse hepatic angiogenic gene expression. Biochem Biophys Res Commun 310:439–445PubMedCrossRefGoogle Scholar
  35. Tran DC, Brazeau DA, Fung HL (2005) Determination of nitric oxide-donor effects on tissue gene expression in vivo using low-density gene arrays. Methods Enzymol 396:387–395PubMedCrossRefGoogle Scholar
  36. Tran DC, Brazeau DA, Nickerson PA, Fung HL (2006) Effects of repeated in vivo inhalant nitrite exposure on gene expression in mouse liver and lungs. Nitric Oxide 14:279–289.PubMedCrossRefGoogle Scholar
  37. Weil A, Rosen W (1993) From chocolate to morphine. Everything you need to know about mind-altering drugs. Houghton Mifflin Company, BostonGoogle Scholar
  38. Wu LT, Schlenger WE, Ringwalt CL (2005) Use of nitrite inhalants (“poppers”) among American youth. J Adolesc Health 37:52–60PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at BuffaloBuffaloUSA

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