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Basic Pharmacology and Toxicology

  • Sara Mostafalou
  • Mohammad AbdollahiEmail author
Chapter

Abstract

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.

Keywords

Pharmacokinetics Toxicokinetics DNA alkylation Thiol adduct Cell cycle arrest Apoptosis Inflammation 

Notes

Glossary

ATP

Adenosine triphosphate

ATSDR

Agency for Toxic Substances and Disease Registry

CWC

Chemical weapon convention

CYP

Cytochrome P450

ERK

Extracellular signal-regulated kinases

IL-1α

Interleukin-1 alpha

IL-1β

Interleukin-1 beta

IL-6

Interleukin-6

IL-8

Interleukin-8

JNK

c-Jun N-terminal kinases

MAPK

Mitogen activated protein kinase

NAD

Nicotinamide adenine dinucleotide

NADP

Nicotinamide adenine dinucleotide phosphate

NOS

Nitric oxide synthase

OPCW

Organization for the Prohibition of Chemical Weapons

PARP

Poly (ADP-ribose) polymerase

SM

Sulfur mustard

TNF-α

Tumor necrosis factor alpha

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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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