Poly polymerase, mustard

Poly(ADP-ribose) polymerase (PADPRP) hypothesis. - In this theory DNA is the initial target of the mustard agent. Alkylated DNA purines undergo spontaneous and enzymatic depurination, leading to the production of apurinic sites which are cleaved by apurinic endonucleases to yield DNA breaks. Accumulation of DNA breaks leads to activation of the chromosomal enzyme PADPRP, which utilizes nicotinamide adenine dinucleotide (NAD ) as a substrate to ADP-ribosylate and a variety of nuclear... 

Rosenthal, D.S., Simhulan-Rosenthal, C.M., Iyer, S., Smith, W.J., Ray, R., Smulson, M.E. (2000). Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard. J. Appl. Toxicol. 20 (Suppl. 1) S43-9. 

Debiak, M., Kehe, K., Burkle, A. (2008). Role of poly(ADP-ribose) polymerase in sulfur mustard toxicity. Toxicology (June 18, Epub ahead of print) doi 10.1016/j.tox.2008.06.002. 

Hinshaw, D.B., Lodhi, I.J., Hurley, L.L., Atkins, K.B., Dabrowska, M.I. (1999). Activation of poly [ADP-ribose] polymerase in endothelial cells and keratinocytes role in an in vitro model of sulfur mustard-mediated vesication. Toxicol. Appl. Pharmacol. 156 17-29. 

Bhat, K.R., Benton, B.J., Ray, R. (2006). Poly (ADP-rihose) polymerase (PARP) is essential for sulfur mustard-induced DNA damage repair, hut has no role in DNA ligase activation. J. Appl. Toxicol. 26 452-7. 

Kehe, K., Raithel, K., Kreppel, H., Jochum, M., Worek, F., Thiermann, H. (2007). Inhibition of poly(ADP-rihose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cells. Arch. Toxicol. 82 461-70. 

Meier, H.L. (1996). The time-dependent effect of 2,2 -dichlor-odiethyl sulfide (sulfur mustard, HD, l,l -thiobis [2-chloro-ethane]) on the lymphocyte viability and the kinetics of protection by poly(ADP-ribose) polymerase inhibitors. Cell. Biol. Toxicol. 12 147-53. 

Meier, H.L., Millard, C.B. (1998). Alterations in human lymphocyte DNA caused by sulfur mustard can be mitigated by selective inhibitors of poly(ADP-ribose) polymerase. Biochim. Biophys. Acta 1404 367-76. 

Meier, H.L., Millard, C., Moser, J. (2000). Poly(ADP-ribose) polymerase inhibitors regulate the mechanism of sulfur mustard-initiated cell death in human lymphocytes. J. Appl. Toxicol 20 S93-100. 

The poly(ADP-ribose) polymerase (PARP) hypothesis in which DNA strand breaks, induced by mustard, activates the nuclear enzyme PARP culminating in metabohc dismp-tion and protease activation in the region of the basal epidermal cells (Papirmeister et al., 1985). 

The account given above is only the briefest summary of the explosion of work on the mechanisms of effect of sulphur mustard that has been published during the past ten or so years. It is clear that Papirmeister s hypothesis linking DNA repair by poly(ADP-ribose) polymerase with a reduction in NAD+ and activation of the hexose monophosphate shunt and subsequent activation of proteases is still plausible. However, so is the apoptosis theory linking as it does with increases in intracellular calcium levels. It has also been shown that sulphur mustard can affect, directly or indirectly, components of the epidermal-basal lamina linkage system and this may explain the blistering effect of this chemical. However, some questions remain ... 

Clark, O.E. and Smith, W.J., Activation of poly(ADP-ribose) polymerase by snlfur mustard in HeLa cell cnltnres, in Proceedings of the 1993 Medical Defense Bioscience Review,... 

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