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Archives of Toxicology (v.75, #7)
No Title by Sheila Schwartz (pp. 381-387).
A package of toxicokinetic and disposition studies is generally conducted in support of reproductive toxicology studies in the development of new drugs. The content of the package often varies between companies and sometimes either insufficient data or inappropriate/over-interpreted data are presented. This paper was written to aid investigators in the design of toxicokinetic and disposition studies in support of reproductive toxicology. It offers: (1) an overview on the regulatory guidelines for toxicokinetics, (2) methods for the derivation of toxicokinetic parameters, (3) suggestions on general toxicokinetic study design, (4) suggestions on the specific design of toxicokinetic support for reproductive toxicology studies, and (5) an overview of species differences in placental transfer and the applicability (or otherwise) of transfer studies in drug development. Toxicokinetic and drug disposition studies should be carefully designed in order to gather relevant information, and consideration should be given to the usefulness of any data before embarking on a series of supporting or routine experiments.
Keywords: Reproductive toxicology Toxicokinetics Pharmaceutical development
No Title by B. Wilhelm; U. Walther; B. Fichtl (pp. 388-394).
Zinc-mediated toxicity has been linked to cellular glutathione (GSH) contents. In this study, effects of zinc on cellular GSH content, glutathione reductase (GR) activity, and GSH synthesis were investigated. In all cell lines tested, decreases in cellular GSH content and GR activity as well as an increase in oxidized glutathione (GSSG) were found after incubation of cells with zinc chloride. These effects were dose- and time-dependent. Changes in GR activities were earliest affected and were most marked compared with the other parameters examined. Decrease of enzyme activity was not due to a decrease in the cosubstrate NADPH. In A549 and L2 cells, initial increases in GSH synthesis rates occurred up to about 175% of control. Later, GSH synthesis decreased to levels below controls. In 16Lu cells, GSH synthesis decreased after 2 h of zinc exposure. No transient increase was found in this cell line. Measurement of ATP content did not show any influence of zinc on cellular ATP. Lactate dehyrogenase leakage, a marker of a clear cytotoxic effect, occurred after 6 h of zinc treatment in the non-malignant cells examined, and after 16 h in malignant A549 cells. We assume the inhibition of GR activity and the associated increase of GSSG could possibly represent a main zinc-mediated toxic cellular effect.
Keywords: A549 Cells L2 Cells 16Lu Cells Inhalational toxicity Zinc toxicity
No Title by Kohji Shimoda; Satoshi Okawara; Michiyuki Kato (pp. 395-399).
We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation. Retinal degeneration was induced at 40 mg/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation. We then examined the incidence of retinal degeneration with various periods of UVA irradiation in BALB/c mice given a single intravenous administration of 40 mg/kg sitafloxacin. Retinal degeneration occurred in all the groups receiving UVA irradiation immediately after sitafloxacin administration, whereas no retinal degeneration occurred in the groups receiving UVA irradiation starting 30 min or later after administration. In addition, we examined both the retinal degeneration and auricular inflammation in BALB/c mice given a 7-day repeated administration of sitafloxacin at 1, 3.3 and 10 mg/kg per day, which never induce retinal or auricular change by a single administration. Retinal degeneration was not induced at any dose level, although auricular skin inflammation was augmented by repeated administration. These results suggest that the occurrence of retinal degeneration depends on maximum ocular sitafloxacin concentration during UVA irradiation, whereas the severity of auricular inflammation is directly proportional to the total decrease in area under the drug concentration curve for auricular sitafloxacin under UVA irradiation. This difference between retinal degeneration and auricular inflammation may derive from their respective mechanisms of pathogenesis.
Keywords: Phototoxicity Quinolone Sitafloxacin Retina Toxicokinetics
No Title by A. Yasutake; K. Hirayama (pp. 400-406).
To examine the demethylation reaction of methylmercury (MeHg) in rat liver, slices prepared from MeHg-treated rats were incubated in L-15 medium under 95% O2/5% CO2 atmosphere. During the incubation, the amount of inorganic Hg in the slices markedly increased in a time-dependent manner, although the concentration of total Hg remained unchanged. Since the C-Hg bond in MeHg was demonstrated to be cleaved by the action of some reactive oxygen species, the effects on MeHg demethylation of several reagents that could modify reactive oxygen production were examined in the present system. Methylviologen was found to be an effective enhancer of the demethylation reaction with only a minor effect on lipid peroxidation. On the other hand, ferrous ion added to the medium showed no effect on demethylation in the presence or absence of methylviologen, although lipid peroxide levels were increased significantly by ferrous ion. Similarly, deferoxamine mesylate, which effectively suppressed the increase in lipid peroxide levels, also had no effect on demethylation. Furthermore, hydroxy radical scavengers, such as mannitol and dimethylsulfoxide, had no effect on inorganic Hg production. Rotenone, an inhibitor of complex I in the mitochondrial electron transport system, increased levels of both inorganic Hg and lipid peroxide. However, other inhibitors, such as antimycin A, myxothiazole and NaCN, significantly suppressed the demethylation reaction. Cell fractionation of the MeHg-treated rat liver revealed that the ratio of inorganic Hg to total Hg was highest in the mitochondrial fraction. Furthermore, superoxide anion could degrade MeHg in an organic solvent but not in water. These results suggested that the demethylation of MeHg by the liver slice would proceed with the aid of superoxide anion produced in the electron transfer system at the hydrophobic mitochondrial inner membrane. Furthermore, the involvement of hydroxy radicals, which have been demonstrated to be effective in cleaving the C-Hg bond in the aqueous media, might be minimal. Here, we also demonstrated that liver slices are a useful experimental model for mimicking the MeHg biotransformation reaction.
Keywords: Methylmercury Biotransformation Reactive oxygen Liver slice Mitochondria
No Title by Neslihan Kocabaş; Ali Karakaya; Suzanne Cholerton; Şemra Şardaş (pp. 407-409).
Catechol O-methyltransferase (COMT) inactivates neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. A low activity allele has been demonstrated at codon 108/158 of the soluble and membrane-bound COMT, respectively, whereby a G to A transition results in a valine to methionine substitution. Ethnic and inter-individual differences in red blood cell COMT activity have been observed in the different populations studied so far. Since, no information is available on inter-individual variability of COMT genotype in Turkish population, we genotyped 217 healthy, unrelated Turkish individuals. The allelic frequencies of COMT gene in the Turkish population were found to be the same as has been observed in Caucasians, but different from Orientals.
Keywords: Catechol-O-methyltransferase Genotype Genetic polymorphism Turkish population
No Title by Maja Peraica; Ana-Marija Domijan; Mirjana Matašin; Ana Lucić; Božica Radić; Frane Delaš; Martina Horvat; Ivanka Bosanac; Melita Balija; Damir Grgičević (pp. 410-414).
The nephrotoxic mycotoxin ochratoxin A (OTA), a common contaminant of cereals, has been implicated in the etiology of endemic nephropathy. It was also frequently found in low concentrations in blood of healthy populations in countries where endemic nephropathy is not known. However, data on regional and seasonal differences in the frequency and concentration of OTA in human blood are scarce. In June, September and December 1997, and March 1998, about 50 human blood samples were collected randomly from blood donors for blood banks in the Coatian cities of Osijek, Rijeka, Split, VaraŽdin and Zagreb. OTA was measured in the total of 983 samples using an HPLC technique with fluorescent detection. The daily intake of OTA was estimated from the mean concentration found in different cities and at different times of year. Samples containing OTA above the detection limit (0.2 ng/ml of plasma) were found in populations from all Croatian cities at all collecting periods. The highest frequency (59%) of samples containing OTA above the detection limit and the highest mean concentration (0.39 ng/ml) were found in June. Both the frequency and the mean concentration were lowest in all samples in December (36% and 0.19 ng OTA/ml, respectively). Osijek was the city with the highest frequency of OTA-positive samples (81%) and the highest mean OTA concentration (0.56 ng/ml). The total mean concentration of OTA in blood of healthy population in Croatia is lower (0.30 ng/ml) than the mean concentration in European countries as a whole (0.90 ng/ml). The estimated daily intake, calculated from the mean concentration in all blood samples, is 0.40 ng OTA/kg body weight, which is much lower than that proposed by World Health Organization as the tolerable daily intake (16.0 ng/kg body weight). Healthy populations of Croatia are exposed to low, but seasonally and regionally variable amounts of OTA.
Keywords: Ochratoxin A Mycotoxin Blood donors Healthy population Croatia Daily intake
No Title by Neil Macdonald; Stephan Chevalier; Robert Tonge; Matthew Davison; Rachel Rowlinson; Janice Young; Steve Rayner; Ruth Roberts (pp. 415-424).
Peroxisome proliferators (PPs) are a diverse group of chemicals that cause hepatic proliferation, suppression of apoptosis, peroxisome proliferation and liver tumours in rodents. The biochemical response to PPs involves changes in the expression of peroxisomal β-oxidation enzymes and fatty acid transport proteins such as acyl-CoA oxidase and liver fatty acid binding protein. The response to PPs is mediated by the peroxisome proliferator-activated receptor α (PPARα) and the livers of PPARα-null transgenic mice do not develop tumours in response to PPs. In order to identify the molecular pathways underlying the adverse effects of PPs in rodent liver, we carried out two-dimensional differential gel electrophoresis to provide quantitative proteomic analyses of diethylhexylphthalate (DEHP)-treated wild-type or PPARα-null mouse livers. Since tumourigenesis is both PP- and PPARα-dependent, analyses were focused on these changes. Fifty-nine proteins were identified where altered expression was both PPARα- and PP-dependent. In addition, six proteins regulated by the deletion of PPARα were identified, possibly indicating an adaptive change in response to the loss of this receptor. The proteins that we identified as being regulated by PPARα are known to be involved in lipid metabolism pathways, but also in amino acid and carbohydrate metabolism, mitochondrial bioenergetics and in stress responses including several genes not previously reported to be regulated by PPARα. These data provide novel insights into the pathways utilised by PPs and may assist in the identification of early markers rodent nongenotoxic hepatocarcinogenesis.
Keywords: Diethylhexylphthalate Peroxisome proliferator Liver Proteome Peroxisome proliferator-activated receptor α Phthalate Proteomics
No Title by Jeffrey R. Haskins; Paul Rowse; Ramin Rahbari; Felix A. de la Iglesia (pp. 425-438).
Thiazolidinediones (TZDs) are effective for the treatment of adult-onset insulin-resistant diabetes. Unfortunately, TZDs are associated with sporadic hepatic dysfunction that is not predictable from experimental animal studies. We investigated the response of isolated rat and human hepatocytes to various TZDs using biochemical assays, coherent multiprobe fluorescence microscopy and flow cytometric analyses. The results identified direct effects of TZD on mitochondria from live human and rodent hepatocytes. The multiprobe fluorescence assays showed disruption of mitochondrial activity as an initiating event followed by increased membrane permeability, calcium influx and nuclear condensation. Other TZD-related cellular effects were increased hepatic enzyme leakage, decreased reductive metabolism and cytoplasmic adenosine triphosphate depletion. Mitochondrial effects were similar in cryopreserved hepatocytes from diabetic or non-diabetic donors. Peripheral blood mononuclear cells (PBMCs) had baseline mitochondrial energetics and metabolism comparable with isolated hepatocytes. Mitochondrial effects in isolated hepatocytes were found in human PBMCs exposed to the TZDs. The relative potency of TZDs for causing hepatocyte and PBMC effects was troglitazone >pioglitazone >rosiglitazone. These studies clearly demonstrated that hepatic alterations in vitro are characteristic of TZDs, with only quantitative differences in subcellular organelle dysfunction. Monitoring mitochondrial function in isolated PBMCs may be beneficial in diabetics undergoing TZD therapy.
Keywords: Thiazolidinediones Peripheral leukocytes In vitro Comparative toxicity Liver