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Archives of Toxicology (v.75, #8)

No Title by Tania Christova; Dessislava Duridanova; Anna Braykova; Milka Setchenska; Thomas Bolton (pp. 445-451).

Changes in the activities of rat liver heme oxygenase (HO), superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione reductase (GR), as well as changes in lipid peroxidation and reduced glutathione (GSH) levels were measured after acute loading and chronic administration of cobalt chloride (CoCl₂). Acute loading was achieved by a single subcutaneous injection of 60 mg CoCl₂/kg body weight for 24 h. Chronic administration was performed by giving the same total amount of CoCl₂ in small doses over longer periods of time: 30 mg CoCl₂/kg daily for 2 days, 15 mg CoCl₂/kg daily for 4 days, or 10 mg CoCl₂/kgdaily for 6 days. The results showed that HO activity was increased both after acute loading (7-fold increase) and upon 6-day administration of CoCl₂ (5-fold increase). The GSH level, 24 h after a single injection of CoCl₂, was lower than that of the control animals. However, upon chronic administration of small doses CoCl₂, the level of GSH increased and was accompanied by an increase in GR activity. Chronic administration of CoCl₂ produced persistent oxidative stress, which was illustrated with a continuous increase in lipid peroxidation. At the same time, under these conditions, the activities of oxidative-stress-protective enzymes were either inhibited (SOD, catalase) or not significantly changed (GPx). Collectively, these findings suggest that the sustained up-regulation of HO activity in rat liver upon 6 day administration of CoCl₂ would be beneficial by providing the cells with antioxidants, biliverdin and bilirubin, and together with the increased levels of GSH would act as a part of the defence mechanisms against the cobalt-induced oxidative stress.

Keywords: Heme oxygenase Oxidative stress Chronic cobalt exposure Antioxidant enzymes

No Title by E. Evdokimova; H. Taper; P. Buc Calderon (pp. 452-458).

The influence of cold storage and reoxygenation at 37°C of precision-cut rat liver slices on paracetamol metabolism was studied. A depressed metabolism was observed after cold preservation, but during reoxygenation at 37°C slices were capable of synthesizing proteins and maintaining both glutathione and ATP levels. Recovery was faster in slices under aerobic cold conditions than in those under cold hypoxia. Glycogen levels were dramatically decreased under both conditions and subsequent reoxygenation at 37°C still increased the glycogenolysis. Xenobiotic metabolism after reoxygenation of cold-preserved slices shows that glucuronide and sulfate conjugates of paracetamol represent about 50% of those of fresh slices at zero time. The amounts of phase II apoproteins were virtually unchanged, thus suggesting that loss of enzyme activities are most probably due to lack of cofactors. Reoxygenation at 37°C did not impair cell metabolism, and a potential role for nitric oxide and other cytokines released form Kupffer cells appears unlikely since nitrite was not formed after bacterial endotoxin stimulation. The maintenance of energetic stores during cold preservation appears, therefore, to be a critical issue for the survival and metabolic activity of cells.

Keywords: Paracetamol metabolism Liver slices Hypoxia-reoxygenation Phase II

No Title by Gökçe A. Törüner; Cemaliye Akyerli; Ahmet Uçar; Tuncay Akı; Necmettin Atsu; Haluk Özen; Mesut Tez; Mesut Çetinkaya; Tayfun Özçelik (pp. 459-464).

We investigated the effect of the GSTM1 and GSTT1 null genotypes, and GSTP1 313 A/G polymorphism on bladder cancer susceptibility in a case control study of 121 bladder cancer patients, and 121 age- and sex-matched controls of the Turkish population. The adjusted odds ratio for age, sex, and smoking status is 1.94 [95% confidence intervals (CI) 1.15–3.26] for the GSTM1 null genotype, and 1.75 (95% CI 1.03–2.99) for the GSTP1 313 A/G or G/G genotypes. GSTT1 was shown not to be associated with bladder cancer. Combination of the two high-risk genotypes, GSTM1 null and GSTP1 313 A/G or G/G, revealed that the risk increases to 3.91-fold (95% CI 1.88–8.13) compared with the combination of the low-risk genotypes of these loci. In individuals with the combined risk factors of cigarette smoking and the GSTM1 null genotype, the risk of bladder cancer is 2.81 times (95% CI 1.23–6.35) that of persons who both carry the GSTM1-present genotype and do not smoke. Similarly, the risk is 2.38-fold (95% CI 1.12–4.95) for the combined GSTP1 313 A/G and G/G genotypes and smoking. These findings support the role for the GSTM1 null and the GSTP1 313 AG or GG genotypes in the development of bladder cancer. Furthermore, gene-gene (GSTM1-GSTP1) and gene-environment (GSTM1-smoking, GSTP1-smoking) interactions increase this risk substantially.

Keywords: Bladder cancer Gene polymorphism Glutathione transferase

No Title by Félix Carvalho; José Duarte; Maria Neuparth; Helena Carmo; Eduarda Fernandes; Fernando Remião; Maria Bastos (pp. 465-469).

The toxicity of amphetamines is conditioned by a complex array of mechanisms, involving the increase of neurotransmission (e.g. leading to hyperthermia) and enzymatic and non-enzymatic oxidation of amphetamines and biogenic amines. Considering that all these processes may increase the generation of hydrogen peroxide (H₂O₂) by metabolic or non-metabolic redox pathways, the main objective of this work was to evaluate d-amphetamine-induced H₂O₂ production in mice liver, kidney and heart. The contribution of monoamine oxidase (MAO) to H₂O₂ production after d-amphetamine administration was studied using the MAO inhibitor pargyline. H₂O₂ production was measured indirectly using the catalase-H₂O₂ complex I irreversible inhibitor 3-amino-1,2,4-triazole (AT). Using this method, the measurement of residual catalase activity following administration of AT permits the monitoring of H₂O₂ production in vivo. Charles River CD-1 mice (30–35 g body weight) were injected with AT just before the injection of d-amphetamine sulphate (20 mg/kg). d-Amphetamine stimulated the production of H₂O₂ in all tissues studied, although to different degrees. MAO inhibition by itself led to a remarkable decrease of basal H₂O₂ production in the kidney and a slight decrease in the liver, although no effect was observed in the heart. d-Amphetamine-induced H₂O₂production in the heart and kidney was reduced in MAO-inhibited mice. However, in the liver, H₂O₂production was transiently potentiated at 30 min under MAO inhibition. In conclusion, d-amphetamine administration leads to an increase in H₂O₂ production in mouse liver, kidney and heart, and monoamine oxidase plays an important role in this effect.

Keywords: d-Amphetamine Catecholamines Adrenergic stimulation Monoamine oxidase Hydrogen peroxide Aminotriazole

No Title by P. Ulrich; O. Grenet; J. Bluemel; H. Vohr; C. Wiemann; O. Grundler; W. Suter (pp. 470-479).

We have investigated the cytokine response pattern following sensitisation (induction) of BALB/c mice with different chemicals (dinitrochlorobenzene, dinitrofluorobenzene, oxazolone, glutaraldehyde, formaldehyde, trimellitic anhydride, croton oil) and elicitation (challenge) of contact allergy in sensitised animals. The results of our investigations showed that different chemicals induced both T helper (Th) 1 cytokines [interleukin (IL) 2, interferon β (IFNβ)] and Th2 cytokines (IL-4, IL-10) at different stages during murine contact allergy. We also confirmed our previous findings that IL-4 and IL-10 release were up-regulated during the challenge phase regardless the contact allergen used, whereas the release of IFNβ did not show a clear preference for being up- or down-regulated. In our hands, the increased expression of Th2 cytokines after challenge exposure to contact allergens appeared as a stable marker of secondary contact allergenic responses. Quantitative differences in the expression of IL-4 were observed between different contact allergens. The present results clearly indicate that skin sensitisers were able to elicit cytokine response patterns, which could not be related to a clear-cut Th1 or Th2 type of cytokine response. Furthermore, dermal application of contact allergens produced different kinetics of cytokine secretion upon induction and challenge. In our hands, the co-expression of Th1 and Th2 type cytokines appeared as a universal consequence of dermal application of contact allergens to responsive mice. Our results indicate that co-expression of Th1 and Th2 cytokines during contact allergy is an important feature of murine contact allergy in responsive mice and that chemicals differ in their potency to induce the expression of these cytokines. Furthermore, the results do not support the view that different chemicals induce Th1 or Th2 cytokines in a mutually exclusive manner depending on their preference for inducing either contact or respiratory allergy. The results are expected to renew the discussion about the usefulness of the Th1/Th2 paradigm in certain areas of immunotoxicology.

Keywords: Contact allergy Contact hypersensitivity Respiratory allergy Irritation Local lymph node assay Cytokines T helper 1 T helper 2

No Title by Robin A. Huff; Aqel W. Abu-Qare; Mohamed B. Abou-Donia (pp. 480-486).

In this study dosing regimens were designed such that cholinesterase inhibition following exposure to chlorpyrifos was produced in one treatment group, but was absent in the other. The higher dosing regimen inhibited plasma and brain cholinesterase activities by 51 and 70%, respectively, and resulted in decreased [³H]cis-methyldioxolane ([³H]CD) binding, which was attributable to a decrease in B _max. No concomitant loss of [³H]quinuclidinyl benzilate ([³H]QNB) binding sites was observed, indicating that the M₂ muscarinic receptor subtype to which [³H]CD binds is particularly susceptible to alterations induced by chlorpyrifos treatment. As the M₂ receptor subtype is surmised to be the muscarinic autoreceptor, decreases in this receptor may exacerbate poisoning by organophosphorus agents as a result of decreased ability to terminate synaptic acetylcholine release. The ability of carbachol to inhibit striatal adenylate cyclase, which is an effector molecule associated with the M₂ receptor, was unaltered in chlorpyrifos-treated rats. Decreases in M₂ receptors occurred with the higher dosing regimen, in the absence of any clinical manifestations. Thus, in the absence of overt clinical signs, perturbations of the muscarinic receptor system did occur as a result of sub-chronic chlorpyrifos exposure. Such alterations may contribute to neurological impairments that develop following chronic organophosphorus exposure.

Keywords: Organophosphates Cholinesterase Insecticide Chlorpyrifos

No Title by David K. Obatomi; Richard O. Blackburn; Peter H. Bach (pp. 487-496).

Atractyloside is a compound with a documented nephrotoxicity. It induces renal tubular necrosis at high doses and apoptosis at lower doses. This study investigates the potential protective effect of some chemical agents against atractyloside-induced nephrotoxicity in vitro using the precision-cut rat renal cortical slices obtained from kidneys of Wistar rats. For co-incubation experiments, slices were incubated for 3 h at 37°C on a rocker platform with various chemical agents: ADP (5 mM), calpain inhibitor I (CPI, 1 mM), stevioside (STV, 2.5 mM) or probenecid (PRB, 2.5 mM) in the presence or absence of atractyloside (2 mM). For pre-incubation experiments, slices were incubated with the same chemical agents for 1 h before exposure to atractyloside. The nephrotoxic effects of atractyloside (2 mM) alone were manifested in several ways: by a marked increase in lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) leakage, significant inhibition of p-aminohippurate (PAH) accumulation, marked depletion of intracellular ATP and reduced glutathione (GSH), and a significant reduction in pyruvate-stimulated gluconeogenesis. Co-incubation of slices with ADP or CPI and atractyloside completely blocked atractyloside-induced increase in LDH leakage, but not ALP leakage. Atractyloside-induced depletion of ATP and reduced gluconeogenesis was prevented by co-incubation with ADP or CPI. Furthermore, co-incubation of slices with STV and atractyloside, but not PRB, completely abolished atractyloside-induced depletion of ATP and decreased gluconeogenesis in the slices. Pre-incubation of slices with either ADP or CPI protected against atractyloside-induced increase in LDH leakage, reduced ATP and decreased gluconeogenesis. PAH uptake in the slices was inhibited by atractyloside and PRB in a time-dependent manner. While ADP and CPI were found to exert complete protection against atractyloside-induced toxicity irrespective of treatment schedule, STV is effective only under certain conditions, and PRB offer no protection at all. The results of this study demonstrate the usefulness of renal cortical slices as toxicology tool for evaluating and screening compounds for their potential protective effects, and are supportive of a role of adeninine nucleotide (ADP) and protease inhibitor (CPI) in protecting against atractyloside-induced cell injury.

Keywords: Atractyloside toxicity Calpain inhibitor I ADP Stevioside Probenecid Nephroprotectants Kidney slices Renal transport

No Title by Ralph Rühl; Jörn Sass; Heinz Nau; Stephan Klug (pp. 497-504).

In vitro systems are widely used to evaluate the embryotoxic potential of retinoids. The effective concentrations of these retinoids, however, are not consistent in the various in vitro systems used in evaluating embryotoxicity. This may be explained by the different level of complexity for each individual system, which may lead to different concentrations of the substances in the target tissues. To verify this hypothesis we have compared two in vitro systems of distinct biological complexity: the rat whole embryo culture system, and the mouse limb bud organ culture system. The lipid soluble, teratogenic retinoid all-trans-retinoic acid (ATRA), and all-trans-retinoyl-β-D-glucuronide (ATRAG), an endogenous, water-soluble and biologically active retinoid with limited placental transfer, were compared with regard to their embryotoxic potential in vitro. In both in vitro systems, ATRAG showed a lower degree of embryotoxicity than ATRA. In the limb bud organ culture, ATRAG revealed only slightly less toxicity than ATRA, whereas the effective concentrations of the two compounds in the whole embryo culture system differed by almost two orders of magnitude. During incubation with ATRAG, ATRA is generated by hydrolysis and is found in culture media and exposed tissues. The presence of membrane barriers around the developing embryo in the whole embryo culture system possibly prevents the transfer of ATRAG to the embryo and, therefore, its exposure to the active hydrolysis product ATRA. From these results we conclude that analysis of retinoid concentrations in the culture media and in the exposed tissues is essential for the interpretation of results obtained from in vitro toxicity testing.

Keywords: Retinoid Limb bud culture Whole embryo culture Teratogenicity Embryotoxicity in vitro Retinoic acid Retinoyl glucuronide

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Archives of Toxicology (v.75, #8)