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Archives of Toxicology (v.78, #11)

Effects of aluminum on phosphate metabolism in rats: a possible interaction with vitamin D₃ renal production by Stella T. Mahieu; Julio Navoni; Néstor Millen; María del Carmen Contini; Marcela Gonzalez; María Mónica Elías (pp. 609-616).

The effect of chronic aluminum (Al) administration on the phosphorous (Pi) metabolism of different target tissues was studied. Male Wistar rats received aluminum lactate for 3 months (5.75 mg/kg bodyweight of Al, i.p., three times per week). The animals were studied at the end of the 1st, 2nd and 3rd month of treatment. They were housed individually in metabolic cages for 4 days to study Pi and calcium (Ca) balance. Daily food and water intakes were recorded for all animals and urine and feces were collected for Pi and calcium assays. After 3 months the Pi intestinal absorption and the Pi deposition in bone were studied using ³²Pi. Another group of rats was treated daily for 7 days with calcitriol (0.08 μg/kg body weight in sesame oil, i.p.) and the Pi balance was studied for the last 4 days. The results indicated that chronic administration of Al affected simultaneously the Pi and calcium balance, with a significant diminution of calcium and increased Pi accretion in bones, together with a diminution in the intestinal absorption of Pi. The treatment of the rats with calcitriol promoted a normalized Pi balance in Al treated rats. These findings suggest that Al could modify the Pi metabolism acting directly on intestine, kidney and bone, or indirectly through possible changes in the levels of vitamin D₃.

Keywords: Aluminum; Phosphorous metabolism; Calcium metabolism; Vitamin D₃

Percutaneous penetration and metabolism of 2-butoxyethanol by David J. Lockley; Douglas Howes; Faith M. Williams (pp. 617-628).

2-Butoxyethanol (2-BE) is widely used as an industrial solvent, which may result in human dermal exposure within the workplace. This study compares in vivo and in vitro skin absorption of 2-BE using similar application regimes and determines the potential of skin to metabolise this chemical prior to entering the systemic blood circulation. Following topical application of undiluted [1-¹⁴C] 2-BE to occluded rat skin in vivo, 28% of the dose was absorbed after 24 h. The major routes of excretion included the urine (19%), expiration as carbon dioxide (6%) and faeces (0.4%) whilst little of the dose remained in the carcass (1.3%). Free 2-BE (0.5%), butoxyacetic acid (8%), glucuronide conjugate (3%), sulphate conjugates (0.7%) and ethylene glycol (0.6%) were detected in urine. Permeation rates of 2-BE through unoccluded rat dermatomed skin (16%) were greater than rat whole skin (8%) whilst absorption through human dermatomed skin (4%) was lower than the rat. Absorption of undiluted 2-BE through occluded rat dermatomed skin in vitro (18%) most accurately predicted absorption through rat skin in vivo. However, 2-BE absorption (23%) was enhanced by application in methanol. Distribution analysis and microautoradiography demonstrated the lack of 2-BE accumulation within the skin in vitro or in vivo. This was reflected in the absence of first pass metabolism of 2-BE during percutaneous penetration through viable human or rat skin in vitro or rat skin in vivo, despite rat skin cytosol having the potential to metabolise 2-BE. In conclusion, the in vitro system provided a reasonable estimate of dermal absorption in vivo for the rat. Therefore, by extrapolation of the comparative in vitro data for human and rat skin in vitro, dermal absorption of 2-BE in man was about one-fifth of that in the rat. However, the rapid penetration through skin in vitro prevented local metabolism and systemic exposure after skin contact with 2-BE in vivo was likely to be to the parent compound. Thus, in vitro skin systems can be used to model dermal absorption of volatile glycol ethers, to predict how much compound enters the circulation and allows the toxicologist to evaluate the body burden of a chemical and potential systemic toxicity.

Keywords: In vivo/in vitro correlation; Percutaneous penetration; 2-Butoxyethanol; Flow through diffusion cell; Occlusion; Microautoradiography

Hydrolysis of carbaryl by human serum albumin by Miguel A. Sogorb; Victoria Carrera; Eugenio Vilanova (pp. 629-634).

Human serum (HS) and human serum albumin (HSA) were able to hydrolyse the carbamate carbaryl. Carbarylase activity found in HSA was slightly activated by 1 mM Zn²⁺, Mn²⁺, Cd²⁺, Ni²⁺ and Na⁺ and by 0.01 mM Pb²⁺. The organophosphorus compounds paraoxon and O-hexyl O-2,5-dichlorophenyl phosphoramidate, caprylic acid, palmitic acid and the carboxyl ester p-nitrophenyl butyrate inhibited the hydrolysis of carbaryl by HSA, being in the last case a competitive inhibition. Using selective amino acid reagents, we concluded that Cys, Trp, Arg and Tyr seem to play important roles in the carbarylase activity of HSA. In addition, Tyr and Arg seem to be located in the active centre of the enzyme since carbaryl protected the activity from the inhibition. It was concluded that HSA hydrolyses carbaryl by a mechanism similar to that described for rabbit serum albumin based in transient carbamylation of a Tyr residue. The extrapolation of the hydrolysis rate to physiological albumin concentrations suggests that albumin might be playing a critical role in the detoxication of carbaryl.

Keywords: Carbamate; Carbaryl; Carboxylesterase; Human serum albumin; Hydrolysis

Relative antioxidant capacities of propofol and its main metabolites by Sandrine Boisset; Jean-Paul Steghens; Patrick Favetta; Raphaël Terreux; Jérôme Guitton (pp. 635-642).

The antioxidant activity of propofol, a widely used anesthetic, has previously been demonstrated, but no study has focused on propofol metabolites although propofol undergoes extensive metabolism. In the present study, the antioxidant properties of propofol and its metabolites were studied by measuring malondialdehyde (MDA) produced from lipid peroxidation by microsomes triggered with several free radical generating systems. True MDA determination was performed using a specific high performance liquid chromatography technique. Gas chromatography–isotope ratio mass spectrometry methodology was also used to assess the antioxidant action in a homogeneous aqueous environment. Propofol, 2,6-di-isopropyl-1,4-quinol (1,4-quinol) metabolite and 3,5-di-tert-butyl-4-hydroxytoluene markedly inhibit lipid peroxidation at concentrations lower than 5 µM. The binding of the glucuroconjugated moiety to either one of two hydroxyl groups of 1,4-quinol lowers the radical scavenging activity. Propofol glucuronide did not exert any radical scavenging activity except when peroxidation was induced with tert-butylhydroperoxide. Our data demonstrate that propofol and its metabolites inhibit lipid peroxidation at concentrations similar to those measured in human plasma during anesthesia. Their antioxidant efficiency is influenced by several factors, including the type of radical initiator involved and the site of radical production.

Keywords: Propofol; Metabolites; Free radicals; Lipid peroxidation; Glucuroconjugate; Scavenging activity

Transforming growth factor β1 is not involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent release from contact-inhibition in WB-F344 cells by Peter Hoelper; Dagmar Faust; Franz Oesch; Cornelia Dietrich (pp. 643-648).

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is the most potent tumor promoter ever tested in rodents. Although it is known that most of the effects of TCDD are mediated by binding to the aryl hydrocarbon receptor (AhR), the mechanisms leading to tumor promotion still remain to be elucidated. Loss of contact-inhibition is one characteristic hallmark in tumorigenesis. In WB-F344 cells, TCDD induces a release from contact-inhibition, which is manifested by a two- to three-fold increase in DNA-synthesis when TCDD (1 nM) is given to confluent cells. Since proliferation of epithelial cells is known to be inhibited by transforming growth factor β (TGF-β) we investigated whether decreased TGF-β expression mediates TCDD-dependent release from contact-inhibition in WB-F344 cells. Expression of TGF-β (type II) receptor in WB-F344 cells was shown by Western blot analysis. Exposure of exponentially growing WB-F344 cells to 0.1 ng/ml TGF-β1 resulted in a 40% decrease in DNA synthesis, which could be blocked by pre-incubation with a neutralizing anti-TGF-β1 antibody indicating that the TGF-β receptor in WB-F344 cells is functionally active. Pre-incubation of confluent, G1-arrested cultures with the neutralizing anti-TGF-β1 antibody did not lead to an increase in DNA synthesis, ruling out an involvement of TGF-β1 in mediating contact-inhibition in WB-F344 cells. In accordance with this, Western blot analysis revealed that protein expression of TGF-β1 was neither upregulated in confluent cultures nor decreased after TCDD treatment. We therefore conclude that TGF-β1 is not involved in contact-inhibition nor in TCDD-dependent release from contact-inhibition in WB-F344 cells.

Keywords: Contact-inhibition; 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); Transforming growth factor β

Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin by Genevieve Choquet-Kastylevsky; Jacques Descotes (pp. 649-654).

The popliteal lymph node (PLN) assay was proposed to detect the potential of immunotoxicants for inducing systemic autoimmune-like reactions, but also xenobiotics that are sensitizing or exert immunostimulatory properties. Results on over 100 chemicals, mostly pharmaceuticals, are available with the PLN assay and show many correlations between rodent data and the clinical experience. A major issue is that the mechanisms involved have not been fully elucidated. In order to provide mechanistic clues to improve the predictability of the PLN assay, the effects of streptozotocin (STZ) were compared to those of ethanol and acetone in normal C57Bl/6 mice as well as mice depleted in CD4⁺ or CD8⁺ T-cells by treatment with specific monoclonal antibodies. STZ, ethanol and acetone gave similar positive responses in normal mice. Neither CD4⁺ nor CD8⁺ T-cell depletion influenced the PLN responses to ethanol or acetone, whereas CD8⁺ in contrast to CD4⁺ T-cell depletion abolished the response to STZ. There was an increase in the production of IL-6 and IFN-γ mRNAs measured by RT-PCR in STZ-, but not in ethanol- or acetone-treated normal mice. The production of TNFα, IL-1α, IL-1β, IL-2R and IL-12 mRNAs was increased whatever the treatment, but increases were 2- to 3-fold greater after STZ than ethanol or acetone. These results suggest that PLN responses to primary irritants such as ethanol and acetone essentially reflect non-specific inflammation, whereas PLN responses to an autoimmunogenic compound such as STZ involve CD8⁺ T lymphocytes and the production of IFN-γ and IL-6. These findings may prove useful to improve the predictability of the PLN assay.

Keywords: Acetone; CD8⁺ T-cells; Ethanol; IFN-γ; IL-6; Mice; PLN assay; Streptozotocin

Vascular wall damage in rats induced by methidathion and ameliorating effect of vitamins E and C by Turhan Yavuz; Namik Delibas; Bekir Yildirim; Irfan Altuntas; Ozden Candır; Ahmet Cora; Nermin Karaman; Erdogan Ibrisim; Ali Kutsal (pp. 655-659).

We examined the effect of subacute methidathion (MD) administration on vascular wall damage and evaluated the ameliorating effects of combination of vitamins E and C against MD toxicity. The experimental groups were: rats treated with corn oil (control group), rats treated with 5 mg/kg MD (MD), and rats treated with 5 mg/kg body weight MD plus vitamin E and vitamin C (MD+Vit). The groups were given MD by gavage on 5 days a week for 4 weeks at a daily dose 5 mg/kg (MD and MD+Vit) using corn oil as the vehicle. Vitamins E and C were injected at doses of 50 mg/kg intramuscularly and 20 mg/kg intraperitoneally, respectively, after the treatment with MD in the MD+Vit group. The levels of malondialdehyde (MDA) were determined in the aortic tissue. Histopathological examination was examined in the thoracic aortic tissue. MDA levels were higher in the MD group than the control group and lower in the MD+Vit group than MD group. MD administration led to irregulation, prominent breaks, and fragmentation of the elastic fibers but decrease in the irregulation and fragmantation of the elastic fibers with the combination of vitamins E and C in MD-treated rats. In conclusion, it is likely that subacute MD administration caused vascular wall damage, and that treatment with a combination of vitamins E and C after the administration of MD can reduce vascular wall damage caused by MD.

Keywords: Methidathion; Vascular wall; Lipid peroxidation; Vitamin E; Vitamin C

Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands by M. M. A. Elmazar; H. Nau (pp. 660-668).

Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21–28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2–9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465–487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARα-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all-trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists.

Keywords: Vitamin A; Retinol; Retinoic acid; Phytol; Phytanic acid; Am580; CD2608; RAR-RXR heterodimerization; Synergistic teratogenesis; Mice; Embryo

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Archives of Toxicology (v.78, #11)