Sulfur mustard-induced microvesication in hairless guinea pigs: effect of short-term niacinamide administration.

Published on Nov 1, 1992in Toxicology and Applied Pharmacology3.347
· DOI :10.1016/0041-008X(92)90223-F
Jeffrey J. Yourick5
Estimated H-index: 5
Jeffrey S. Dawson3
Estimated H-index: 3
Larry W. Mitcheltree12
Estimated H-index: 12
Abstract It has been postulated that sulfur mustard (HD) damage may activate poly(ADP-ribose) polymerase (PADPRP), resulting in depletion of cellular NAD + . This biochemical alteration is postulated to result in blister (vesicle) formation. It has been previously demonstrated that niacinamide (NAM), an inhibitor of PADPRP and a precursor for NAD + synthesis, may be useful as a pretreatment compound to reduce HD-induced microvesication. The present study was undertaken to determine whether niacinamide's protective action could be extended beyond 24 hr and if the degree of microvesication is related to changes in skin NAD + content. HD exposures were made by vapor cup to hairless guinea pigs. Niacinamide (750 mg/kg, ip) given as a 30-min pretreatment did not reduce the degree of microvesication 72 hr after HD compared to saline controls. However, niacinamide given as a 30-min pretreatment and at 6-, 24-, and 48-hr after HD, exhibited a 28% reduction in microvesication 72 hr after HD. Skin NAD + content at 72 hr after HD was depleted by approximately 53% in the saline and NAM-treated groups. Skin NAD + content was depleted despite NAM administration. Niacinamide did not reduce the degree of erythema at 48 or 72 hr. These results suggest that niacinamide's protective effect against HD-induced microvesication may be extended for at least 72 hr, but NAM levels must be sustained during the post-HD period. The link between maintenance of skin NAD + and reductions in microvesication is still uncertain.
📖 Papers frequently viewed together
69 Citations
86 Citations
267 Citations
Abstract 2,2′-Dichlorodiethyl sulfide (sulfur mustard, HD, 1,1′-thiobis[2-chloroethane]) is a potent vesicant which can cause severe lesions to skin, lung, and eyes. There is no convenient in vitro or in vivo method(s) to objectively measure the damage induced by HD; therefore, a simple in vitro method was developed using human peripheral lymphocytes to study HD-induced cytotoxicity. The cytotoxicity of HD was measured using dye exclusion as an indicator of human lymphocyte viability. Exposure t...
49 CitationsSource
#1Nabil M. ElsayedH-Index: 15
#2Stanley T. OmayeH-Index: 26
Last. Don W. KorteH-Index: 5
view all 4 authors...
Vesicant-induced pathogenesis is initiated by rapid alkylation and cross-linking of DNA purine bases causing strand breaks leading subsequently to NAD depletion and cell death. We postulated that vesicants may also be associated with free radical-mediated oxidative stress distal to the site of exposure. To test this postulate in the lung, we injected 3 groups (n = 8) of 5-month-old, male, athymic, nude mice, weighing 30–35 g with a single subcutaneous (s.c.) injection (5 μl/mouse) of butyl 2-chl...
65 CitationsSource
#1Lan JornotH-Index: 12
#2Hilke PetersenH-Index: 5
Last. Alain JunodH-Index: 53
view all 3 authors...
The respective roles of H2O2 and ·OH radicals was assessed from the protective effects of catalase and the iron chelator o-phenanthroline on (1) the inhibition of protein synthesis, and (2) DNA damage and the related events (activation of the DNA repairing enzyme poly(ADP) ribose polymerase with the associated depletion of NAD and ATP stores) in cultured endothelial cells exposed to the enzyme reaction hypoxanthine-xanthine oxidase (HX-XO) or pure H2O2. Catalase added in the extracellular phase ...
23 CitationsSource
#1Jeffrey J. Yourick (United States Army Medical Research Institute of Chemical Defense)H-Index: 1
#2Connie R. Clark (United States Army Medical Research Institute of Chemical Defense)H-Index: 1
Last. Larry W. Mitcheltree (United States Army Medical Research Institute of Chemical Defense)H-Index: 4
view all 3 authors...
It has been proposed that sulfur mustard (HD) may indirectly activate poly(ADP-ribose) polymerase (PADPRP) by alkylating cellular DNA (Papirmeister et al., 1985). Activation of PADPRP results in the depletion of cellular NAD+, which initiates a series of biochemical processes that have been proposed to culminate in blister formation. Preventing PADPRP activation and NAD+ depletion should inhibit blister formation. Niacinamide is both an inhibitor of PADPRP and a precursor for NAD+ synthesis. The...
69 CitationsSource
These experiments are a continuation of work investigating the mechanism of oxidant-induced damage to cultured bovine pulmonary artery endothelial cells (BPEC). Earlier experiments implicated DNA strand breakage and activation of poly(ADP-ribose)polymerase as critical steps in cell injury. In the current report, a better defined model of oxidant stress was used to investigate DNA damage, lipid peroxidation and protein thiol oxidation in BPEC following oxidant stress. The dose and time response o...
110 CitationsSource
Abstract Blister formation due to sulfur mustard (HD) exposure was studied in an ex vivo human skin model. Pieces of fresh human skin were exposed to HD vapor and subsequently incubated in medium for 48 hr. During this culture period cellular NAD + levels and uptake of glucose from the medium decreased relative to the duration of the exposure to HD. In light microscopic sections of skin that were exposed to HD for 6 min, clefts of variable size could be clearly observed between the epidermis and...
49 CitationsSource
#1Millard M. MershonH-Index: 6
Last. John V. WadeH-Index: 4
view all 5 authors...
Abstract Sulfur mustard (HD; 1,1′-thiobis[2-chloroethane]) induces fluid-filled blisters in man but not in conventional laboratory animals. An animal model is needed to emulate both cytotoxic (vesicant) and vascular (irritant) responses of human skin to HD exposures. An acceptable model must permit reproducible comparisons of uniformly graded and dose-related HD control responses with reduced responses that may follow antivesicant treatments. Hairless guinea pigs were evaluated by exposing six o...
86 CitationsSource
#1William J. SmithH-Index: 20
#2Clark L. GrossH-Index: 11
Last. Henry Louis Meier (DA: United States Department of the Army)H-Index: 11
view all 4 authors...
Human epidermal keratinocytes in culture were studied to evaluate their usefulness in demonstrating toxic events following exposure to sulfur mustard. Exposure of keratinocytes to sulfur mustard over a concentration range of 1–1000 μM HD, reduced NAD+ levels from 96% to 32% of control levels. When keratinocytes were exposed to a concentration of 300 μM HD, NAD+ levels began to fall at 1 hour and reached a plateau of 47% of control levels at 4 hours. Niacinamide, an inhibitor of the enzyme poly(A...
69 CitationsSource
#1Johan J.P. Gille (UvA: University of Amsterdam)H-Index: 42
#2C.G.M. van Berkel (UvA: University of Amsterdam)H-Index: 11
Last. Hans Joenje (UvA: University of Amsterdam)H-Index: 79
view all 5 authors...
Abstract Cell death by oxidative stress has been proposed to be based on suicidal NAD depletion, typically followed by ATP depletion, caused by the NAD-consuming enzyme poly(ADP)ribose polymerase, which becomes activated by the presence of excessive DNA-strand breaks. In this study NAD + , NADH and ATP levels as well as DNA-strand breaks (assayed by alkaline elution) were determined in Chinese hamster ovary (CHO) cells treated with either H 2 O 2 or hyperoxia to a level of more than 80% clonogen...
35 CitationsSource
In cultured human epidermal cells exposure to the vesicant sulfur mustard (HD) causes a decrease of the NAD+ content, which depends on the dose and the time period between exposure to HD and NAD+ measurement. Presumably, this NAD+ loss is due to activation of the enzyme NAD:protein ADP-ribosyltransferase (ADPRT) and may lead to glycolysis inhibition, disturbance of energy metabolism, and eventually cell death. Since prevention of this NAD+ depletion could lead to cell survival, HD-exposed cultur...
68 CitationsSource
Cited By23
#1Joanna A. Ruszkiewicz (University of Konstanz)H-Index: 2
#2Alexander Bürkle (University of Konstanz)H-Index: 4
Last. Aswin Mangerich (University of Konstanz)H-Index: 18
view all 3 authors...
Abstract Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the...
1 CitationsSource
#1Leila Etemad (MUMS: Mashhad University of Medical Sciences)H-Index: 10
#2Mohammad Moshiri (MUMS: Mashhad University of Medical Sciences)H-Index: 10
Last. Mahdi Balali-Mood (Birjand University of Medical Sciences)H-Index: 4
view all 3 authors...
AbstractSulfur mustard (SM) is a blistering chemical warfare agent that was used during the World War I and in the Iraq–Iran conflict. The aim of this paper is to discuss and critically review the ...
8 CitationsSource
#1Mostafa Ghanei (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 39
#2Ali Amini Harandi (Shahid Beheshti University of Medical Sciences and Health Services)H-Index: 19
Despite ongoing investigations in the treatment of patients exposed to mustard gas, treatment in the acute phase is still nonspecific and there is no appropriate antidote. The best treatment options in this stage are primary prevention and detoxification. Considering the nature of imbalance between oxidant and antioxidant systems in chemical patients, one of the most important objectives of future treatments is to use drugs that can help to restore the lost balance.
#4Robert P. Casillas (Battelle Memorial Institute)H-Index: 20
This chapter describes the dermal toxicity events of the alkylating agent, sulfur mustard [bis(2-chloroethyl) sulfide], which ultimately causes detachment of the epidermis from the dermis. Skin exposure to sulfur mustard (SM) starts a series of dermal toxicity events with severity determined in part by mediators of injury that regulate inflammation, immune responses, apoptosis, necrosis, and a number of signaling pathways. This complex series of events involves a host of normal skin responses to...
4 CitationsSource
#1Masoud Maleki (MUMS: Mashhad University of Medical Sciences)H-Index: 11
#2Pouran Layegh (MUMS: Mashhad University of Medical Sciences)H-Index: 11
The skin is one of the important affected target organs by sulfur mustard (SM) as a chemical weapon, besides the eyes and lungs. Skin exposure with sulfur mustard results in the onset of a multiple series of events including a full set of dermal responses for normal wound healing and their mutual influence on each other, eventually leading to skin toxicity. In this process, various mediators that have a regulating role in inflammation, apoptosis, immune responses and some signaling pathways are ...
#1Zohreh Poursaleh (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 10
#2Ali Amini Harandi (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 19
Last. Mostafa Ghanei (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 39
view all 4 authors...
Objective Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One ...
36 CitationsSource
#2Anshoo GautamH-Index: 11
Last. Manoj SharmaH-Index: 64
view all 3 authors...
Publisher Summary Chemically, sulfur mustard (SM) is bis (2-chloroethyl) sulfide and is well known as mustard gas. There are various mustard agents. However, SM is one of the most important blistering or vesicating agents. SM forms sulfonium ion in the body and alkylates DNA leading to DNA strand breaks and cell death. Due to the high electrophilic property of the sulfonium ion, SM binds to a variety of cellular macromolecules. The most common complications of SM occur in lung, skin, and eye, wh...
9 CitationsSource
#1Donald R. GereckeH-Index: 18
#2Joshua P. GrayH-Index: 19
Last. Robert P. CasillasH-Index: 20
view all 4 authors...
Publisher Summary This chapter deals with the cutaneous actions of sulfur mustard (SM) and discusses the basic mechanism of action and mediators involved. While stable in lipophilic solvents, SM has a half life of only 24 min at room temperature in aqueous physiological solutions, since it rapidly reacts with water to form thiodiglycol and HCl. This rapid activation of SM in an aqueous environment also allows it to react with small molecules of biological interest, as well as proteins, carbohydr...
1 CitationsSource
Niacinamide (aka nicotinamide) and Niacin (aka nicotinic acid) are heterocyclic aromatic compounds which function in cosmetics primarily as hair and skin conditioning agents. Niacinamide is used in around 30 cosmetic formulations including shampoos, hair tonics, skin moisturizers, and cleansing formulations. Niacin is used in a few similar product types. The concentration of use of Niacinamide varies from a low of 0.0001 % in night preparations to a high of 3% in body and hand creams, lotions, p...
51 CitationsSource
#1Richard AmataH-Index: 1
#2Dolores A. BebloH-Index: 1
Last. Zemoria A. RosemondH-Index: 1
view all 3 authors...
10 Citations