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Archives of Toxicology (v.82, #7)


Family 1 uridine-5′-diphosphate glucuronosyltransferases (UGT1A): from Gilbert’s syndrome to genetic organization and variability by Christian P. Strassburg; Tim O. Lankisch; Michael P. Manns; Ursula Ehmer (pp. 415-433).
The human UDP-glucuronosyltransferase 1A gene locus is organized to generate enzymes, which share a carboxyterminal portion and are unique at their aminoterminal variable region. Expression is tissue-specific and overlapping substrate specificities include a broad spectrum of endogenous and xenobiotic compounds as well as many therapeutic drugs targeted for detoxification and elimination by glucuronidation. The absence of glucuronidation leads to fatal hyperbilirubinemia. A remarkable interindividual variability of UDP-glucuronosyltransferases is evidenced by over 100 identified genetic variants leading to alterations of catalytic activites or transcription levels. Variant alleles with lower carcinogen detoxification activity have been associated with cancer risk such as colorectal cancer and hepatocellular carcinoma. Genetic variants and haplotypes have been identified as risk factors for unwanted drug effects of the anticancer drug irinotecan and the antiviral proteinase inhibitor atazanavir. Glucuronidation and its variability are likely to represent an important factor for individualized drug therapy and risk prediction impacting the drug development and licensing processes.

Keywords: Pharmacogenetics; Gilbert’s syndrome; UGT1A7; Carcinogenesis; Drug safety; Glucuronidation


A new in vitro cellular system for the analysis of mineral fiber biopersistence by Hermine Dika Nguea; Aymon de Reydellet; Patrice Lehuédé; Alain de Méringo; Anne Robé; Alain Le Faou; Bertrand H. Rihn (pp. 435-443).
The toxicity of mineral fibers, whether they are natural or man made (MMMF), is usually evaluated in vivo using biopersistence tests in rodents. Development of an in vitro cellular model would be worthwhile in order to reduce, refine and finally replace animal models. For this purpose, we developed an in vitro assay using human monocytic cell line (U-937) to evaluate a new manufactured rock wool fiber (HDN) biodegradation. Experiments on earlier known mineral fibers asbestos (crocidolite) and glass wool fibers (CM44) were also performed. U-937 responded to HDN and CM44 only if they were activated. Among the different activators we used, Escherichia coli living cells as well as FS were the most efficient as evidenced by alterations of HDN and CM44 surface, detected by scanning electron microscopy, and by the measure of silicon released from the rock wool fibers. Asbestos fibers were not degraded when incubated in the presence of living bacteria. The MMMF modifications were function of the fiber composition, the time of exposure to activated cells and the concentration of activators. The pattern of MMMF degradation by our in vitro system was in accordance with those observed in an in vivo study, thus indicating that the fiber degradation by macrophage cells activated by E. coli living cells as well as FS is a valuable system to assess mineral fibers’ biopersistence.

Keywords: Rock wool fibers; Glass wool fibers; Asbestos fibers; Human monocyte activation; Biopersistence; Escherichia coli


Behavioral impairments related to lead-induced developmental neurotoxicity in chicks by Yara M. R. Müller; Lilianna B. D. Rivero; Márcia C. Carvalho; Karoline Kobus; Marcelo Farina; Evelise M. Nazari (pp. 445-451).
Lead intoxication affects the central nervous system and produces structural disorders and behavioral deficits in several animal species. Although lead neurotoxicity is a well-reported phenomenon, studies on the developmental neurotoxicity induced by this metal in avian are scarce. The aim of this study was to evaluate how a single dose of 28 μg lead acetate administered into the yolk sac on the fifth incubation day of Gallus domesticus can affect the behavior and the brain tissue in the first postnatal week. Several behavioral tests, mainly those related to the motor and exploratory functions were evaluated at fifth and sixth postnatal days (PN). The lead deposition into mesencephalon and cerebellum was investigated by autometallography (AMG) method. Congenital anomalies, as failure on closure of body’s ventral midline and leg dysfunction, were observed in treated chicks. During the first postnatal week, inactivity and anomalous movements were significantly high in lead treated chicks in comparison to control animals. Lead impregnation was observed in both mesencephalon and cerebellum and the cerebellar molecular layer presented higher lead deposition in comparison to granular layer and Purkinje cells. Our results indicate that the in ovo exposure to lead induces important deficits on motor behavior of chicks during the first postnatal week and such phenomena are related to lead deposition in the cerebellar tissue during embryonic development. The proposed exposure schedule represents an interesting experimental approach for studding behavioral and cellular mechanisms related to lead-induced developmental neurotoxicity.

Keywords: Chick embryo; Lead poisoning; Behavioral tests; Nervous system; Cerebellum


Effects of in utero meso-2,3-dimercaptosuccinic acid with calcium and ascorbic acid on lead-induced fetal development by Fei Yu; Yingjun Liao; Yaping Jin; Yue Zhao; Yahao Ren; Chunwei Lu; Gexin Li; Yanxi Li; Jun Yang (pp. 453-459).
To examine the effects of meso-2,3-dimercaptosuccinic acid (DMSA) on developmental toxicity resulting from exposure to lead in utero, female albino mice were exposed to lead by drinking water contaminated with lead acetate for 4 weeks. After the cessation of lead exposure, female mice were supplemented by gavage with saline solution, DMSA, or DMSA and calcium as well as ascorbic acid from the fourth day of gestation until parturition, respectively. Lead levels (blood, liver, and bone) were measured at birth. Pups were then tested about neural development including surface righting reflex, cliff avoidance and air righting reflex. The markers of physical maturation, such as body weight, pinna unfolding, incisor eruption, and eye opening were also recorded. DMSA treatment decreased blood lead levels of pregnant mice, however, increased lead levels in both liver and bone of fetus, and delayed the early physical and neural development of offspring. Calcium and ascorbic acid reduced the transfer of lead to fetus. In conclusion, DMSA treatment during pregnancy enhances lead-induced fetal developmental toxicity.

Keywords: Meso-2,3-dimercaptosuccinic acid (DMSA); Calcium; Ascorbic acid; Lead; Pregnancy; Fetus; Development


Inhibition of poly(ADP-ribose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cells by K. Kehe; K. Raithel; H. Kreppel; M. Jochum; F. Worek; H. Thiermann (pp. 461-470).
Sulfur mustard (SM) is a bifunctional alkylating agent. Its primary toxic consequence is severe skin damage with blisters, occurring after skin contact. These vesicant properties of SM have been linked to cell death of proliferating keratinocytes in the basal layer of the skin. Catalytic activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) has been demonstrated to be a major event in response to high levels of DNA damage, and PARP-1 activation may be part of apoptotic signaling. In other contexts, overstimulation of PARP-1 triggers necrotic cell death because of rapid consumption of its substrate, β-nicotinamide adenine dinucleotide (NAD+) and the consequent depletion of ATP. These findings prompted us to evaluate whether SM induces apoptosis in keratinocytes like HaCaT cells and to determine whether blocking of PARP enzyme activity with 3-aminobenzamide (3AB) can influence the mode of cell death. HaCaT cells were exposed to SM (10-1,000 μM; 30 min) and then cultivated in SM-free medium with or without 3AB for up to 48 h. This treatment resulted in a time and SM dose-dependent increase of apoptotic cell death characterized by PARP-1 cleavage and DNA fragmentation during the experimental period. After just 45 min of exposure to 1 mM SM, we observed a significant increase in PARP-1 activity in HaCaT cells. About 6 h after exposure, intracellular ATP levels were diminished by 22%, which seemed to be completely prevented by the addition of 3AB directly after exposure. However, 18 h later, this 3AB effect on the SM concentration-dependent loss of ATP was no longer detectable. Interestingly, the effect of SM on total cell viability was not changed by 3AB. However, the mode of cell death was influenced by 3AB exhibiting an increase of apoptotic cells and a concomitant decrease of necrotic HaCaT cells during the first 24 h after SM exposure. Our results indicate that SM concentrations of 1 mM or higher induce a prominent PARP activation leading to ATP depletion and necrosis. In contrast, lower concentrations of SM cause minor PARP activation and, especially, PARP-1 cleavage by caspase 3 without ATP depletion. Because ATP is required for apoptosis, we suggest that ATP acts as an early molecular switch from apoptotic to necrotic modes of SM-induced cell death, at least at high concentrations (≥1 mM). Thus, the observed early proapoptotic effect of 3AB at lower SM concentrations may point to the influence of ATP-independent cell-death regulating mechanisms.

Curcumin attenuates indomethacin-induced oxidative stress and mitochondrial dysfunction by Nageswaran Sivalingam; Jayasree Basivireddy; Kunissery A. Balasubramanian; Molly Jacob (pp. 471-481).
Oxidative stress and mitochondrial dysfunction have been implicated in the pathogenesis of indomethacin-induced enteropathy. We evaluated the potential of curcumin, a known cytoprotectant, as an agent to protect against such effects. Rats were pretreated with curcumin (40 mg/kg by intra-peritoneal injection) before administration of indomethacin (20 mg/kg by gavage). One hour later, the small intestine was isolated and used for assessment of parameters of oxidative stress. Mitochondria, brush border membranes (BBM) and surfactant-like particles (SLP) were also isolated from the tissue. Mitochondria were used for assessment of functional integrity, estimation of products of lipid peroxidation and lipid content. BBM were used for estimation of products of lipid peroxidation and lipid content, while the SLP were used for measurement of lipid content. The results showed that oxidative stress and mitochondrial dysfunction occurred in the small intestine of indomethacin-treated rats. Pre-treatment with curcumin was found to ameliorate these drug-induced changes. Significant changes were seen in some of the lipids in the mitochondria, BBM and SLP in response to indomethacin. However, curcumin did not have any significant effect on these drug-induced changes. We conclude that curcumin, by attenuating oxidative stress and mitochondrial dysfunction, holds promise as an agent that can potentially reduce NSAID-induced adverse effects in the small intestine.

Keywords: Antioxidants; Curcumin; Mitochondria; Anti-inflammatory agents; Non-steroidal; Oxidative stress; Small intestine
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