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TiiasnaariafictifotitaeModulation of these signaling pathways may offer new therapeu-tic approaches for limiting neuroinflammation in PD and relateddisorders.

doi:10.1016/j.toxlet.2009.06.027

22 Abstracts / Toxicology L

27/5-1, Di 402/9-1, SFB 773 TP B02) and the German Federal Min-stry of Education & Research (BMBF: 02S8416).

oi:10.1016/j.toxlet.2009.06.023

04-05ltraviolet light induced DNA damage that triggers apoptosisathways

arlos F.M. Menck ∗, Tatiana G. Ortolan

Universidade de São Paulo, Inst. of Biomedical Sciences, Departmentf Microbiology, Sao Paulo, Brazil

ltraviolet (UV) light causes severe damages in the DNA moleculehat are efficient obstacles to RNA transcription and DNA replica-ion. Both processes may trigger signals that lead to cell death,

ainly by apoptosis, in human cells. We have investigated theamaging effects of UVC and UVB in primary human fibroblastseficient in DNA repair. Confluent cells were analyzed and the dataemonstrated that apoptosis is reduced in this condition, althoughranscription blockage is affected as in proliferating cells, and, curi-usly, p53 is activated. On the other hand, synchronized cells werenvestigated after UVB irradiation at G1-phase of cell cycle. Dosesmployed were either high enough to trigger apoptosis or suffi-iently low to induce only low frequency of apoptotic cells. Evenn cells with different DNA repair abilities, one common featurebserved was that low UVB doses caused only delays in cell cyclerogression, while higher UVB doses, which triggered apoptosis,aused consistent cell blockage, in G1 or early S-phase. These dosesaried clearly with the DNA repair ability of these cells, and p53nduction corresponded to the levels of apoptosis induction. Curi-usly, however, the induction of MDM2 protein was similar in DNAepair deficient (XP-C) or proficient cells. This protein acts as aegative regulator of p53, but these results indicate that MDM2

nduction is not the main factor determining cell evasion fromVB-induced apoptosis. Moreover, the data suggest that blockagef S-phase progression is a crucial step in apoptosis induction byVB DNA lesions in primary human cells.

oi:10.1016/j.toxlet.2009.06.024

ymposium 5: Nitrative and Oxidative Stress in Toxicology andisease

05-01eroxynitrite: Biochemistry, toxicology and development ofherapeutics

saba Szabo

The University of Texas Medical Branch, Department ofnesthesiology Building, Galveston, United States

eroxynitrite, the product of the diffusion-controlled reaction ofitric oxide with superoxide, is a short-lived oxidant species that

s a potent inducer of apoptosis and necrosis and is an upregula-or of certain pro-inflammatory pathways. Conditions in which theeaction products of peroxynitrite have been detected and in which

ts pharmacological neutralization has been shown to be of bene-t include vascular diseases, reperfusion injury, circulatory shock,

nflammation and neurodegeneration. Peroxynitrite formation haslso been demonstrated in response to exposure to various environ-

189S (2009) S16–S36

ental toxins. Several drugs used in medicine and agriculture exertheir toxic side effects through mechanisms involving the forma-ion of peroxynitrite, via redox cycling, uncoupling of nitric oxideynthase, stimulation of the endogenous formation of nitric oxidend superoxide or lowering of the antioxidant defenses. The rolef peroxynitrite has been demonstrated to play an important rolen the toxicity of doxorubicin, paraquat, acetaminophen and MPTP.eroxynitrite-mediated toxicity can be ameliorated by decreasinghe levels of the precursor radicals (i.e. using NOS inhibitors or SOD

imetics) or reducing the levels of peroxynitrite itself (peroxyni-rite scavengers or decomposition catalysts). These approaches canerve to attenuate or neutralize some of the drug-induced toxi-ities. There are a number of endogenous compounds (vitamins,ntioxidants) that can mitigate some of the deleterious effects oferoxynitrite. In this lecture, we first review the biochemistry andathophysiology of peroxynitrite and then focus on pharmacolog-

cal strategies to attenuate the toxic effects of peroxynitrite (e.g.atalytic reduction to nitrite and its isomerization to nitrate byetalloporphyrins).

oi:10.1016/j.toxlet.2009.06.026

05-02itrative stress and glial–neuronal interactions in the patho-enesis of Parkinson’s disease

on Tjalkens

Colorado State University, Centre for Environmental Medicine, Fortollins, United States

he etiology of Parkinson’s disease (PD) remains controversial butncreasing evidences indicate that persistent neuroinflammationnfluences disease progression. Activation of both microglia andstrocytes is associated with long-term neuroinflammation andustained expression of inflammatory genes, such as inducibleitric oxide (NOS2) and tumor necrosis factor-alpha, that are dam-ging to neurons. Expression of NOS2, in particular, is closelyssociated with enhanced nitration of proteins in midbrain neu-ons from PD patients. Astrocytes have diverse and critical functionsn the central nervous system that include providing energetic,ntioxidant, and other trophic support essential for the survival andunction of neurons but their deleterious role in neuroinflammatorynjury is under increasing scrutiny. Activated astrocytes are notedlinically in PD and have been associated with increased aggrega-ion of alpha-synuclein and loss of dopaminergic neurons. Diversenflammatory cytokines and stress signals converge on the nuclearactor kappa beta (NFkB) signaling pathway to induce expressionf NOS2 and other inflammatory genes in astrocytes and activa-ion of NFkB stimulates astrogliosis in vivo and in vitro, resultingn increased neuronal protein nitration and apoptosis. Transcrip-ional activation of NOS2 by NFkB requires chromatin remodelingnd removal of transcriptional repressor proteins, which is influ-nced by endogenous and exogenous factors that regulated NFkB.