Basic Pharmacology and Toxicology

  • Sara Mostafalou
  • Mohammad AbdollahiEmail author


Sulfur mustards are well absorbed through inhalational, dermal, and ocular contacts and tend to distribute mostly to the lungs, liver, and kidneys. DNA and protein adducts are the main metabolites of sulfur mustards which are mainly excreted in the urine along with unchanged compounds. Sine nitrogen mustards have never been used as chemical warfare, their kinetic information are mostly related to those which have been used as chemotherapeutic agents. Upon absorption through intravenous or oral administration, nitrogen mustards are rapidly converted to their reactive metabolites and distributed so that the highest concentration can be found in bone marrows. Mono-alkylation of guanine at N7 and then N3 respectively give the main DNA adducts of nitrogen mustards. In an aqueous environment, mustard compounds convert to very active electrophilic metabolites which can attack nucleophilic groups in the structure of cellular macromolecules. DNA alkylation is known as the main mechanism by which mustard compounds exert their both toxic and therapeutic effects. They can also alkylate other nucleophils, most notably thiol groups in the structure of proteins, leading to excessive production of reactive oxygen species in the cell. Following the disruption of such functional macromolecules, a series of maladaptive responses are activated, including excessive production of reactive oxygen species and inflammatory cytokines, metabolic imbalance in energy production, elevated release of calcium into the cytosol from intracellular and extracellular sources, and consequently the expression of enzymes involved in necrotic or apoptotic cell death pathways.


Pharmacokinetics Toxicokinetics DNA alkylation Thiol adduct Cell cycle arrest Apoptosis Inflammation 




Adenosine triphosphate


Agency for Toxic Substances and Disease Registry


Chemical weapon convention


Cytochrome P450


Extracellular signal-regulated kinases


Interleukin-1 alpha


Interleukin-1 beta






c-Jun N-terminal kinases


Mitogen activated protein kinase


Nicotinamide adenine dinucleotide


Nicotinamide adenine dinucleotide phosphate


Nitric oxide synthase


Organization for the Prohibition of Chemical Weapons


Poly (ADP-ribose) polymerase


Sulfur mustard


Tumor necrosis factor alpha


  1. ATSDR (2003) Toxicological profile for sulfur mustard (update). Agency for Toxic Substances and Disease Registry, AtlantaGoogle Scholar
  2. Axelrod DJ, Hamilton JG (1947) Radio-autographic studies of the distribution of lewisite and mustard gas in skin and eye tissues. Am J Pathol 23:389–411PubMedPubMedCentralGoogle Scholar
  3. Bhatia U, Danishefsky K, Traganos F, Darzynkiewicz Z (1995) Induction of apoptosis and cell cycle-specific change in expression of p53 in normal lymphocytes and MOLT-4 leukemic cells by nitrogen mustard. Clin Cancer Res: off J Am Assoc Cancer Res 1:873–880Google Scholar
  4. Brunton LL, Parker KL (eds) (2008) Goodman and Gilman’s manual of pharmacology and therapeutics. McGraw-Hill Companies, New YorkGoogle Scholar
  5. Gilman A (1963) The initial clinical trial of nitrogen mustard. Am J Surg 105:574–578CrossRefPubMedGoogle Scholar
  6. Hambrook JL, Howells DJ, Schock C (1993) Biological fate of sulphur mustard (1,1′-thiobis(2chloroethane)): uptake, distribution and retention of 35S in skin and in blood after cutaneous application of 35S-sulphur mustard in rat and comparison with human blood in vitro. Xenobiotica 23:637–661CrossRefGoogle Scholar
  7. Husain K, Dube SN, Sugendran K, Singh R, Das Gupta S, Somani SM (1996) Effect of topically applied sulphur mustard on antioxidant enzymes in blood cells and body tissues of rats. J Appl Toxicology: JAT 16:245–248CrossRefPubMedGoogle Scholar
  8. Kehe K, Balszuweit F, Steinritz D, Thiermann H (2009) Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering. Toxicology 263:12–19CrossRefPubMedGoogle Scholar
  9. Korkmaz A, Yaren H, Topal T, Oter S (2006) Molecular targets against mustard toxicity: implication of cell surface receptors, peroxynitrite production, and PARP activation. Arch Toxicol 80:662–670CrossRefPubMedGoogle Scholar
  10. Mattes WB, Hartley JA, Kohn KW (1986) DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards. Nucleic Acids Res 14:2971–2987CrossRefPubMedPubMedCentralGoogle Scholar
  11. Maynard RL (2007) Mustard Gas. In: Marrs TC, Maynard RL, Sidell FR (eds) Chemical warfare agents toxicology and treatment. Wiley, ChichesterGoogle Scholar
  12. Papirmeister B, Gross CL, Petrali JP, Hixson CJ (1984) Pathology produced by sulfur mustard in human skin grafts on athymic nude mice. I. Gross and light microscopic changes. Cutan Ocul Toxicol 3:371–391CrossRefGoogle Scholar
  13. Papirmeister B, Gross CL, Meier HL, Petrali JP, Johnson JB (1985) Molecular basis for mustard-induced vesication. Fundam and Appl Toxicol: off J Soc Toxicol 5:S134–S149CrossRefGoogle Scholar
  14. Peng GW, Marquez VE, Driscoll JS (1975) Potential central nervous system antitumor agents. Hydantoin derivatives. J Med Chem 18:846–849CrossRefPubMedGoogle Scholar
  15. Ray R, Legere RH, Majerus BJ, Petrali JP (1995) Sulfur mustard-induced increase in intracellular free calcium level and arachidonic acid release from cell membrane. Toxicol Appl Pharmacol 131:44–52CrossRefPubMedGoogle Scholar
  16. Razavi S, Salamati P, Saghafinia M, Abdollahi M (2012) A review on delayed toxic effects of sulfur mustard in Iranian veterans. Daru 20(1):51CrossRefGoogle Scholar
  17. Rosenthal DS, Simbulan-Rosenthal CM, Iyer S, Spoonde A, Smith W, Ray R, Smulson ME (1998) Sulfur mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a Ca2 + −calmodulin and caspase-dependent pathway. J Invest Dermatol 111:64–71CrossRefPubMedGoogle Scholar
  18. Schnyder J, Baggiolini M (1980) Induction of plasminogen activator secretion in macrophages by electrochemical stimulation of the hexose monophosphate shunt with methylene blue. Proc Natl Acad Sci U S A 77:414–417CrossRefPubMedPubMedCentralGoogle Scholar
  19. TOXNET (2004) Mechlorethamine. U.S. National Library of Medicine, Maryland.
  20. TOXNET (2013) BIS(2-Chloroethyl)sulfide. U.S. National Library of Medicine, Maryland.
  21. Vijayaraghavan R, Sugendran K, Pant SC, Husain K, Malhotra RC (1991) Dermal intoxication of mice with bis(2-chloroethyl)sulphide and the protective effect of flavonoids. Toxicology 69:35–42CrossRefPubMedGoogle Scholar
  22. Young RA, Bast C (2009) Mustards and vesicants. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents. Academic, LondonGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.School of PharmacyArdabil University of Medical SciencesArdabilIran
  2. 2.Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research CenterTehran University of Medical SciencesTehranIran
  3. 3.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran

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