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Archives of Toxicology (v.84, #10)
Organic anion transporter 5 renal expression and urinary excretion in rats exposed to mercuric chloride: a potential biomarker of mercury-induced nephropathy by Gisela Di Giusto; Adriana Mónica Torres (pp. 741-749).
Mercuric chloride (HgCl2) induces acute kidney injury (AKI) affecting glomerular hemodynamics and, more specifically, the pars recta (S3 segment) of the proximal tubule. The organic anion transporter 5 (Oat5) is exclusively localized in the apical membranes of S3 segment. Oat5 urinary excretion was recently proposed as potential early biomarker of ischemic AKI. The aim of this study was to evaluate the renal expression and the urinary excretion of the Oat5 in rats exposed to HgCl2. Male Wistar rats were treated with a single injection of HgCl2 at different doses of 0, 0.2, 1 and 5 mg/kg body wt (control, Hg0.2, Hg1 and Hg5 groups). The renal expression of Oat5 was evaluated by immunohistochemistry, Western blotting, and real-time PCR. Oat5 and sodium dicarboxylate cotransporter 1 (NaDC1) abundances and alkaline phosphatase activity (AP) were assayed in urine. An HgCl2 dose-related decrease in Oat5 mRNA levels and in Oat5 protein levels in renal homogenates was observed. Hg5 rats showed an increase in urinary excretion of Oat5 and NaDC1 as well as alterations of other widely used parameters for renal dysfunction and injury (plasma creatinine, plasma urea, urinary AP activity, kidney weight, histological lesions). In Hg0.2 group only an increase of urinary excretion of Oat5 was observed. The increase of Oat5 urinary excretion in Hg1 group was associated to the beginning of tissular injury. These results suggest that urinary excretion of Oat5 might be an early indicator of mercury-induced nephropathy, which predicts the perturbation before the manifestation of histopathological damages.
Keywords: AKI; Mercuric nephrotoxicity; Oat5; NaDC1; Urinary biomarkers
Phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for mechanism-based inhibition of cytochrome P450 by Nattaya Konsue; Costas Ioannides (pp. 751-759).
Phenethyl isothiocyanate is a chemopreventive phytochemical present in cruciferous vegetables where it exists as the glucosinolate gluconasturtiin. It is a mechanism-based inhibitor of both rat and human cytochrome P450 enzymes. The principal objective of the present study was to ascertain whether phenethyl isocyanate, formed by the cytochrome P450-mediated oxidative desulphuration of phenethyl isothiocyanate, is the metabolite responsible for the mechanism-based inhibition. Phenethyl isothiocyanate, following incubation with Aroclor 1254-induced rat liver microsomes in the presence of NADPH, markedly suppressed the CYP1A-mediated O-deethylation of ethoxyresorufin; extent of inhibition was directly related to the pre-incubation time and was antagonised by reduced glutathione. When human liver microsomes were used, the inhibitory effect of phenethyl isothiocyanate, which was once again related to the pre-incubation time, was even more pronounced. When the ability of phenethyl isothiocyanate and phenethyl isocyanate to directly inhibit the O-deethylation of ethoxyresorufin in rat microsomes was compared, the latter compound was only moderately more effective. In human microsomes, both compounds were equipotent. In phenobarbital-induced lung microsomes, phenethyl isothiocyanate was a direct and potent inhibitor of the O-depentylation of pentoxyresorufin; pre-incubation of the isothiocyanate had no impact. Human precision-cut liver slices were more effective than rat slices in metabolising phenethyl isothiocyanate. Pre-treatment of rats, however, with phenobarbitone significantly enhanced the metabolism of isothiocyanate. It may be inferred from the present studies that: (a) phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for its mechanism-based inhibition, and (b) CYP2B is an important catalyst of the metabolism of phenethyl isothiocyanate.
Keywords: Phenethyl isothiocyanate; Isothiocyanates; Mechanism-based inhibition; Cytochrome P450; Chemoprevention
The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism by V. Naidoo; L. Venter; K. Wolter; M. Taggart; R. Cuthbert (pp. 761-766).
In a safety study, Cape Griffon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of ~1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUCinf, Vz and Cl being 10.42 μg/ml h, 0.37 l/kg and 0.10 l/h kg, respectively. Toxicity occurred in the 5 mg/kg group, with 7 of the 11 birds dying. Clinical signs of toxicity included depression, loss of appetite and apparent coma. Animals died within 48 h of dosing. The AUCinf, Vz and Cl in the birds that survived were 52.26 μg/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUCinf, Vz and Cl in the birds those died were 207.90 μg/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUCinf and Cmax in the birds that died, we surmise that toxicity resulted from saturation of the metabolic process. While the exact metabolic pathway remains unknown in these vultures, we believe that toxicity may be due to pharmacogenomic differences in the cytochrome P450 pathway.
Keywords: Ketoprofen; Vulture conservation; Diclofenac; Cape Griffon vulture; NSAID
Amounts and proportion of administered pyrene dose excreted as urinary 1-hydroxypyrene after dietary exposure to polycyclic aromatic hydrocarbons by Yeh-Chung Chien; Chun-Ting Yeh (pp. 767-776).
Although urinary 1-hydroxypyrene (1-OHP) is the most relevant parameter for assessing exposure to polycyclic aromatic hydrocarbons, the inability to further elucidate the intra- and inter-individual variability, specificity and kinetics makes it difficult to enhance its value as an exposure predictor. Therefore, this human control study examined the excretion kinetics of urinary 1-OHP after consuming barbecued meat. Two feeding experiments were conducted, with doses of 15 and 30 g of barbecued meat per kg of body weight for experiments 1 and 2, respectively. All voided urine was collected for 7 days and analyzed for 1-OHP. In both experiments, the amounts of urinary 1-OHP excreted was significantly increased (P < 0.05) at 12 h post exposure but not at 12–24 h post exposure. Mean percentages of administered pyrene doses excreted as urinary 1-OHP at 0–12 h and 12–24 h post exposure were 3.80 and 0.61% in experiment 1 and 1.66 and 0.38% in experiment 2. Excretion ratio was inversely related to dose. A pattern of diurnal fluctuation (P < 0.05) in 1-OHP excretions was also identified. That is, 1-OHP excretions were smaller in the first half of the day (~0:00–12:00) than in the last half of the day (~12:00–24:00). This study demonstrated that, even at large dietary doses, most of the total urinary excretion of 1-OHP occurs within 12 h. Thus, subjects of occupational or environmental studies need only recall their diets for the current or previous day to diminish the influence from dietary pyrene.
Keywords: Barbecued meats; PAH; 1-Hydroxypyrene; Excretion kinetics
Evaluation of the effects and mechanisms of action of glufosinate, an organophosphate insecticide, on striatal dopamine release by using in vivo microdialysis in freely moving rats by Brenda V. Ferreira Nunes; Rafael Durán; Miguel Alfonso; Iris Machado de Oliveira; Lilian R. Ferreira Faro (pp. 777-785).
The purpose of the present work was to assess the effects of glufosinate ammonium (GLA), an aminoacid structurally related to glutamate, on in vivo dopamine (DA) release from rat striatum, using brain microdialysis coupled to HPLC-EC. Intrastriatal administration of GLA produced significant concentration-dependent increases in DA levels. At least two mechanisms can be proposed to explain these increases: GLA could be inducing DA release from synaptic vesicles or producing an inhibition of DA transporter (DAT). Thus, we investigated the effects of GLA under Ca++-free condition, and after pretreatment with reserpine and TTX. It was observed that the pretreatment with Ca++-free Ringer, reserpine or TTX significantly reduced the DA release induced by GLA. Coinfusion of GLA and nomifensine shows that the GLA-induced DA release did not involve the DAT. These results show that GLA-induced striatal DA release is probably mediated by an exocytotic-, Ca++-, action potential-dependent mechanism, being independent of DAT.
Keywords: Glufosinate ammonium; In vivo dopamine release; Brain microdialysis; Rat striatum; HPLC-EC
Hepatocellular hypertrophy and cell proliferation in Sprague–Dawley rats following dietary exposure to ammonium perfluorooctanoate occurs through increased activation of the xenosensor nuclear receptors PPARα and CAR/PXR by Clifford R. Elcombe; Barbara M. Elcombe; John R. Foster; David G. Farrar; Reinhard Jung; Shu-Ching Chang; Gerald L. Kennedy; John L. Butenhoff (pp. 787-798).
Ammonium perfluorooctanoate (APFO), a processing aid used in the production of fluoropolymers, produces hepatomegaly and hepatocellular hypertrophy in rodents. In mice, APFO-induced hepatomegaly is associated with increased activation of the xenosensor nuclear receptors, PPARα and CAR/PXR. Although non-genotoxic, chronic dietary treatment of Sprague–Dawley (S–D) rats with APFO produced an increase in benign tumours of the liver, acinar pancreas, and testicular Leydig cells. Most of the criteria for establishing a PPARα-mediated mode of action for the observed hepatocellular tumours have been previously established with the exception of the demonstration of increased hepatocellular proliferation. The present study evaluates the potential roles for APFO-induced activation of PPARα and CAR/PXR with respect to liver tumour production in the S-D rat and when compared to the specific PPARα agonist, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy 14,643). Male S-D rats were fed APFO (300 ppm in diet) or Wy 14,643 (50 ppm in diet) for either 1, 7, or 28 days. Effects of treatment with APFO included: decreased body weight; hepatomegaly, hepatocellular hypertrophy, hepatocellular hyperplasia (microscopically and by BrdU labelling index), and hepatocellular glycogen loss; increased activation of PPARα (peroxisomal β-oxidation and microsomal CYP4A1 protein); decreased plasma triglycerides, cholesterol, and glucose; increased activation of CAR (CYP2B1/2 protein) and CAR/PXR (CYP3A1 protein). Responses to treatment with Wy 14,643 were consistent with increased activation of PPARα, specifically: increased CYP4A1 and peroxisomal β-oxidation; increased hepatocellular hypertrophy and cell proliferation; decreased apoptosis; and hypolipidaemia. With the exception of decreased apoptosis, the effects observed with Wy 14,643 were noted with APFO, and APFO was less potent. These data clearly demonstrate an early hepatocellular proliferative response to APFO treatment and suggest that the hepatomegaly and tumours observed after chronic dietary exposure of S-D rats to APFO likely are due to a proliferative response to combined activation of PPARα and CAR/PXR. This mode of action is unlikely to pose a human hepatocarcinogenic hazard.
Keywords: Ammonium perfluorooctanoate; PPARα; CAR; PXR; PFOA; Hepatomegaly
Evaluation of the cytotoxic and antimutagenic effects of biflorin, an antitumor 1,4 o-naphthoquinone isolated from Capraria biflora L by Marne C. Vasconcellos; Dinara J. Moura; Renato M. Rosa; Miriana S. Machado; Temenouga N. Guecheva; Izabel Villela; Bruna F. Immich; Raquel C. Montenegro; Aluísio M. Fonseca; Telma L. G. Lemos; Maria Elisabete A. Moraes; Jenifer Saffi; Letícia V. Costa-Lotufo; Manoel O. Moraes; João A. P. Henriques (pp. 799-810).
Biflorin is a natural quinone isolated from Capraria biflora L. Previous studies demonstrated that biflorin inhibits in vitro and in vivo tumor cell growth and presents potent antioxidant activity. In this paper, we report concentration-dependent cytotoxic, genotoxic, antimutagenic, and protective effects of biflorin on Salmonella tiphymurium, yeast Saccharomyces cerevisiae, and V79 mammalian cells, using different approaches. In the Salmonella/microsome assay, biflorin was not mutagenic to TA97a TA98, TA100, and TA102 strains. However, biflorin was able to induce cytotoxicity in haploid S. cerevisiae cells in stationary and exponential phase growth. In diploid yeast cells, biflorin did not induce significant mutagenic and recombinogenic effects at the employed concentration range. In addition, the pre-treatment with biflorin prevented the mutagenic and recombinogenic events induced by hydrogen peroxide (H2O2) in S. cerevisiae. In V79 mammalian cells, biflorin was cytotoxic at higher concentrations. Moreover, at low concentrations biflorin pre-treatment protected against H2O2-induced oxidative damage by reducing lipid peroxidation and DNA damage as evaluated by normal and modified comet assay using DNA glycosylases. Our results suggest that biflorin cellular effects are concentration dependent. At lower concentrations, biflorin has significant antioxidant and protective effects against the cytotoxicity, genotoxicity, mutagenicity, and intracellular lipid peroxidation induced by H2O2 in yeast and mammalian cells, which can be attributed to its hydroxyl radical-scavenging property. However, at higher concentrations, biflorin is cytotoxic and genotoxic.
Keywords: Biflorin; Naphthoquinone; Yeast; V79 cells; Antimutagenic activity; Salmonella/microsome assay
Lutein improves antioxidant defense in vivo and protects against DNA damage and chromosome instability induced by cisplatin by Juliana Mara Serpeloni; Denise Grotto; Adriana Zerlotti Mercadante; Maria de Lourdes Pires Bianchi; Lusânia Maria Greggi Antunes (pp. 811-822).
Lutein (LT) is the second most prevalent carotenoid in human serum, and it is abundantly present in dark, leafy green vegetables. The objectives of this study were to evaluate the genotoxicity and mutagenicity of LT, and its protective effects in vivo against DNA damage and chromosome instability induced by cisplatin (cDDP). For this purpose, we used the comet assay and micronucleus (MN) test, and we evaluated the antioxidant effects of LT by determination of enzymatic (catalase—CAT) and non-enzymatic (reduced glutathione—GSH) activity. Mice were divided into six groups: cDDP, mineral oil (OM), LT groups and LT + cDDP groups. To perform the MN test on peripheral blood (PB) cells, blood samples were collected before the first treatment (T0), and 36 h (T1) and 14 days (T2) after the first treatment. To perform the comet assay, blood samples were collected 4 h after the first and the last treatment. Oxidative capacity was analyzed in total blood that was collected 24 h after the last treatment, when bone marrow (BM) sample was also collected for the MN test. No genotoxic or mutagenic effects of LT were observed for the doses evaluated. We did find that this carotenoid was able to reduce the formation of crosslinks and chromosome instability induced by cDDP. No differences were observed in CAT levels, and LT treatment increased GSH levels compared with a negative control group, reinforcing the role of this carotenoid as an antioxidant.
Keywords: Lutein; Cisplatin; Micronucleus test; Comet assay; Antioxidant biomarkers