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Archives of Toxicology (v.80, #1)
Zinc: a multipurpose trace element by M. Stefanidou; C. Maravelias; A. Dona; C. Spiliopoulou (pp. 1-9).
Zinc (Zn) is one of the most important trace elements in the body and it is essential as a catalytic, structural and regulatory ion. It is involved in homeostasis, in immune responses, in oxidative stress, in apoptosis and in ageing. Zinc-binding proteins (metallothioneins, MTs), are protective in situations of stress and in situations of exposure to toxic metals, infections and low Zn nutrition. Metallothioneins play a key role in Zn-related cell homeostasis due to their high affinity for Zn, which is in turn relevant against oxidative stress and immune responses, including natural killer (NK) cell activity and ageing, since NK activity and Zn ion bioavailability decrease in ageing. Physiological supplementation of Zn in ageing and in age-related degenerative diseases corrects immune defects, reduces infection relapse and prevents ageing. Zinc is not stored in the body and excess intakes result in reduced absorption and increased excretion. Nevertheless, there are cases of acute and chronic Zn poisoning.
Keywords: Zinc; Metallothioneins; Zinc supply; Ageing; Antioxidants; Zinc toxicity
Zinc: a multipurpose trace element by M. Stefanidou; C. Maravelias; A. Dona; C. Spiliopoulou (pp. 1-9).
Zinc (Zn) is one of the most important trace elements in the body and it is essential as a catalytic, structural and regulatory ion. It is involved in homeostasis, in immune responses, in oxidative stress, in apoptosis and in ageing. Zinc-binding proteins (metallothioneins, MTs), are protective in situations of stress and in situations of exposure to toxic metals, infections and low Zn nutrition. Metallothioneins play a key role in Zn-related cell homeostasis due to their high affinity for Zn, which is in turn relevant against oxidative stress and immune responses, including natural killer (NK) cell activity and ageing, since NK activity and Zn ion bioavailability decrease in ageing. Physiological supplementation of Zn in ageing and in age-related degenerative diseases corrects immune defects, reduces infection relapse and prevents ageing. Zinc is not stored in the body and excess intakes result in reduced absorption and increased excretion. Nevertheless, there are cases of acute and chronic Zn poisoning.
Keywords: Zinc; Metallothioneins; Zinc supply; Ageing; Antioxidants; Zinc toxicity
Subacute oral toxicity study of diethylphthalate based on the draft protocol for “Enhanced OECD Test Guideline no. 407” by Keiji Shiraishi; Katusi Miyata; Satsuki Houshuyama; Nobuya Imatanaka; Takaaki Umano; Yasushi Minobe; Kanji Yamasaki (pp. 10-16).
We performed a 28-day repeated-dose toxicity study of diethylphthalate based on the draft protocol of the “Enhanced OECD Test Guideline 407” to investigate whether it has endocrine-mediated properties according to this assay. Diethylphthalate was orally administered to SD rats at doses of 0, 40, 200, and 1,000 mg/kg/day for at least 28 days, but no endocrine-mediated effects were detected based on any of the parameters examined, suggesting that diethylphthalate does not possess endocrine properties according to this assay.
Keywords: Diethylphthalate; Enhanced Test Guideline 407; Rat; Endocrine effects
Subacute oral toxicity study of diethylphthalate based on the draft protocol for “Enhanced OECD Test Guideline no. 407” by Keiji Shiraishi; Katusi Miyata; Satsuki Houshuyama; Nobuya Imatanaka; Takaaki Umano; Yasushi Minobe; Kanji Yamasaki (pp. 10-16).
We performed a 28-day repeated-dose toxicity study of diethylphthalate based on the draft protocol of the “Enhanced OECD Test Guideline 407” to investigate whether it has endocrine-mediated properties according to this assay. Diethylphthalate was orally administered to SD rats at doses of 0, 40, 200, and 1,000 mg/kg/day for at least 28 days, but no endocrine-mediated effects were detected based on any of the parameters examined, suggesting that diethylphthalate does not possess endocrine properties according to this assay.
Keywords: Diethylphthalate; Enhanced Test Guideline 407; Rat; Endocrine effects
Selective metabolism of E-3,4-bis(4-ethylphenyl)hex-3-ene in rat liver microsomes by Eric J. Fabian; Manfred Metzler (pp. 17-26).
The synthetic stilbene derivative E-3,4-bis(4-ethylphenyl)hex-3-ene (E-DE-BPH) has been proposed as a potential anticancer drug with a new mode of action. We report here on the in vitro metabolism of E-DE-BPH in liver microsomes of rats and pigs. The formation of five metabolites, which could be separated on a reverse-phase HPLC column with UV detection, was observed in microsomal incubations. To facilitate the structural identification of these metabolites, two different deuterium-labeled forms of E-DE-BPH were synthesized. By comparing the mass spectra obtained for the metabolites of unlabeled E-DE-BPH and of the two deuterated forms, it could be demonstrated that E-DE-BPH was oxidized by liver microsomes exclusively at the benzylic positions of the molecule. The major metabolite was identified as E-3-(4-(1-hydroxyethyl)phenyl)-4-(4-ethylphenyl)hex-3-ene. Four minor metabolites were formed from the major metabolite, either by hydroxylation at the other benzylic position to yield a bishydroxylated metabolite, or by oxidation of the hydroxyl group to form E-3-(4-acetylphenyl)-4-(4-ethylphenyl)hex-3-ene. The latter compound was also obtained by chemical oxidation of the monohydroxylated metabolite of E-DE-BPH. Since no products containing hydroxyl groups at the aromatic rings or at other aliphatic sites of the molecule were detected, a surprisingly selective oxidative metabolism of E-DE-BPH appears to occur with rat and pig liver microsomes.
Keywords: In vitro metabolism; Liver microsomes; 3,4-Bis(4-ethylphenyl)hex-3-ene; Stilbene
Selective metabolism of E-3,4-bis(4-ethylphenyl)hex-3-ene in rat liver microsomes by Eric J. Fabian; Manfred Metzler (pp. 17-26).
The synthetic stilbene derivative E-3,4-bis(4-ethylphenyl)hex-3-ene (E-DE-BPH) has been proposed as a potential anticancer drug with a new mode of action. We report here on the in vitro metabolism of E-DE-BPH in liver microsomes of rats and pigs. The formation of five metabolites, which could be separated on a reverse-phase HPLC column with UV detection, was observed in microsomal incubations. To facilitate the structural identification of these metabolites, two different deuterium-labeled forms of E-DE-BPH were synthesized. By comparing the mass spectra obtained for the metabolites of unlabeled E-DE-BPH and of the two deuterated forms, it could be demonstrated that E-DE-BPH was oxidized by liver microsomes exclusively at the benzylic positions of the molecule. The major metabolite was identified as E-3-(4-(1-hydroxyethyl)phenyl)-4-(4-ethylphenyl)hex-3-ene. Four minor metabolites were formed from the major metabolite, either by hydroxylation at the other benzylic position to yield a bishydroxylated metabolite, or by oxidation of the hydroxyl group to form E-3-(4-acetylphenyl)-4-(4-ethylphenyl)hex-3-ene. The latter compound was also obtained by chemical oxidation of the monohydroxylated metabolite of E-DE-BPH. Since no products containing hydroxyl groups at the aromatic rings or at other aliphatic sites of the molecule were detected, a surprisingly selective oxidative metabolism of E-DE-BPH appears to occur with rat and pig liver microsomes.
Keywords: In vitro metabolism; Liver microsomes; 3,4-Bis(4-ethylphenyl)hex-3-ene; Stilbene
Miltefosine decreases the cytotoxic effect of Epirubicine and Cyclophosphamide on mouse spermatogenic, thymic and bone marrow cells by Yordanka Martinova; Margarita Topashka-Ancheva; Spiro Konstantinov; Svetlozara Petkova; Margarita Karaivanova; Martin Berger (pp. 27-33).
A new class of potent anticancer drugs, alkylphosphocholines has been recognized lately. Miltefosine (Hexadecylphosphochlorine, HPC) has been found to express select antineoplastic effect on human breast cancer skin metastases with simultaneous preservation of bone marrow proliferative activity and low clastogenicity. In the current study, we present data about the specific effect of two widely used cytostatics Cyclophosphamide (CP) and Epirubicine (ERb) applied separately or in combination with Miltefosine. C57BL6 mice were treated per os or intraperitonieally in doses corresponding to that in clinical use. Morphological, autoradiographic, ultrastructural and cytogenetic studies on spermatogenic, thymic and bone marrow cells were performed. It is found that compared with separate application, combinations of ERb or CP with Miltefosine slightly decreases spermatogonial proliferation and exerts milder effect on the structure of germinal and thymic cells. In addition, a lot of plasmocytes showed signs of active protein (antibody) synthesis. A significant reduction of aberrant chromosomes (clastogenicity) without changes in proliferative activity of bone marrow cells were recorded. In conclusion, the combine application of Miltefosine with ERb and CP decreased the destructive cytotoxic effects of ERb and CP on mouse spermatogenic and hematopoietic cells.
Keywords: Miltefosine; Spermatogenic cells; Thymus; Chromosomes
Miltefosine decreases the cytotoxic effect of Epirubicine and Cyclophosphamide on mouse spermatogenic, thymic and bone marrow cells by Yordanka Martinova; Margarita Topashka-Ancheva; Spiro Konstantinov; Svetlozara Petkova; Margarita Karaivanova; Martin Berger (pp. 27-33).
A new class of potent anticancer drugs, alkylphosphocholines has been recognized lately. Miltefosine (Hexadecylphosphochlorine, HPC) has been found to express select antineoplastic effect on human breast cancer skin metastases with simultaneous preservation of bone marrow proliferative activity and low clastogenicity. In the current study, we present data about the specific effect of two widely used cytostatics Cyclophosphamide (CP) and Epirubicine (ERb) applied separately or in combination with Miltefosine. C57BL6 mice were treated per os or intraperitonieally in doses corresponding to that in clinical use. Morphological, autoradiographic, ultrastructural and cytogenetic studies on spermatogenic, thymic and bone marrow cells were performed. It is found that compared with separate application, combinations of ERb or CP with Miltefosine slightly decreases spermatogonial proliferation and exerts milder effect on the structure of germinal and thymic cells. In addition, a lot of plasmocytes showed signs of active protein (antibody) synthesis. A significant reduction of aberrant chromosomes (clastogenicity) without changes in proliferative activity of bone marrow cells were recorded. In conclusion, the combine application of Miltefosine with ERb and CP decreased the destructive cytotoxic effects of ERb and CP on mouse spermatogenic and hematopoietic cells.
Keywords: Miltefosine; Spermatogenic cells; Thymus; Chromosomes
An oral carcinogenicity and toxicity study of senna (Tinnevelly senna fruits) in the rat by J. M. Mitchell; U. Mengs; S. McPherson; J. Zijlstra; P. Dettmar; R. Gregson; J. C. Tigner (pp. 34-44).
Senna (Tinnevelly senna fruits), a known laxative derived from plants, was administered by gavage to Sprague-Dawley (Crl:CD® (SD) BR) rats once daily at dose levels of 0, 25, 100 and 300 mg/kg/day for up to 104 consecutive weeks. Based upon clinical signs related to the laxation effect of senna, the highest dose (300 mg/kg/day) was considered to be a maximum tolerated dose. Sixty animals per sex were assigned to the control and dose groups. Assessments included clinical chemistry, hematology, full histology (control and high-dose groups; in addition, low and mid dose: intestinal tract, adrenals, liver, kidneys, brain and gross lesions) and toxicokinetics. The primary treatment-related clinical observation was mucoid feces seen at 300 mg/kg/day. When compared to controls, animals administered 300 mg/kg/day had slightly reduced body weights, increased water consumption and notable changes in electrolytes in serum (increases in potassium and chloride) and urine (decreases in sodium, potassium and chloride). The changes in electrolytes are most likely physiologic adaptations to the laxative effect of senna. At necropsy, dark discoloration of the kidneys was observed in animals in all treated groups. Histological changes were seen in the kidneys of animals from all treated groups and included slight to moderate tubular basophilia and tubular pigment deposits. In addition, for all treated groups, minimal to slight hyperplasia was evident in the colon and cecum. These histological changes, together with the changes seen in the evaluation of clinical chemistry and urine parameters, have been shown to be reversible in a previous 13-week rat study of senna. No treatment-related neoplastic changes were observed in any of the examined organs. Based upon these data, it is concluded that senna is not carcinogenic even after daily administration for 2 years at dosages of up to 300 mg/kg/day in Sprague-Dawley rats.
Keywords: Senna; Tinnevelly senna fruits; Anthranoids; Toxicology; Carcinogenicity; Rat
An oral carcinogenicity and toxicity study of senna (Tinnevelly senna fruits) in the rat by J. M. Mitchell; U. Mengs; S. McPherson; J. Zijlstra; P. Dettmar; R. Gregson; J. C. Tigner (pp. 34-44).
Senna (Tinnevelly senna fruits), a known laxative derived from plants, was administered by gavage to Sprague-Dawley (Crl:CD® (SD) BR) rats once daily at dose levels of 0, 25, 100 and 300 mg/kg/day for up to 104 consecutive weeks. Based upon clinical signs related to the laxation effect of senna, the highest dose (300 mg/kg/day) was considered to be a maximum tolerated dose. Sixty animals per sex were assigned to the control and dose groups. Assessments included clinical chemistry, hematology, full histology (control and high-dose groups; in addition, low and mid dose: intestinal tract, adrenals, liver, kidneys, brain and gross lesions) and toxicokinetics. The primary treatment-related clinical observation was mucoid feces seen at 300 mg/kg/day. When compared to controls, animals administered 300 mg/kg/day had slightly reduced body weights, increased water consumption and notable changes in electrolytes in serum (increases in potassium and chloride) and urine (decreases in sodium, potassium and chloride). The changes in electrolytes are most likely physiologic adaptations to the laxative effect of senna. At necropsy, dark discoloration of the kidneys was observed in animals in all treated groups. Histological changes were seen in the kidneys of animals from all treated groups and included slight to moderate tubular basophilia and tubular pigment deposits. In addition, for all treated groups, minimal to slight hyperplasia was evident in the colon and cecum. These histological changes, together with the changes seen in the evaluation of clinical chemistry and urine parameters, have been shown to be reversible in a previous 13-week rat study of senna. No treatment-related neoplastic changes were observed in any of the examined organs. Based upon these data, it is concluded that senna is not carcinogenic even after daily administration for 2 years at dosages of up to 300 mg/kg/day in Sprague-Dawley rats.
Keywords: Senna; Tinnevelly senna fruits; Anthranoids; Toxicology; Carcinogenicity; Rat
Expression of cytochrome P450 enzymes CYP1A1, CYP1B1, CYP2E1 and CYP4B1 in cultured transitional cells from specimens of the human urinary tract and from urinary sediments by P. H. Roos; R. Belik; W. Föllmann; G. H. Degen; H. J. Knopf; H. M. Bolt; K. Golka (pp. 45-52).
Expression of cytochromes P450 CYP1A1, CYP1B1, CYP2E1 and CYP4B1 was analysed on the transcript level in human urothelial cells obtained by various methods. As a source of urothelial cells, exfoliated cells in urine samples were used. Their expression profiles were determined either immediately after centrifugal enrichment (n=4) or after their cultivation and propagation (n=8). Another source of urothelial cells were ureter specimens from surgical subjects (n=4). Generally, expression was most prominent for CYP1B1 and CYP4B1 among the CYP transcripts analysed. CYP1B1 mRNA was detected in all samples investigated except for one ureter specimen. CYP4B1 mRNA was present in cell cultures from three out of eight healthy subjects, in three out of four directly investigated urinary sediments and in the cells of all five ureter specimens of four donors investigated after resection and subsequent cell culture. In most cases, CYP2E1 transcript levels were lower than those of CYP1B1 and CYP4B1. CYP2E1 mRNA was detected in cell cultures of six out of eight healthy subjects, in one out of four urinary sediments and in three out of five ureter specimens. CYP1A1 mRNA was clearly observed only in cells from resected ureters. In cell cultures the relative mRNA expression levels varied with subjects interindividually, intraindividually and also during the time of cell culture. The study demonstrates constitutive mRNA expressions of xenobiotic metabolising CYP enzymes in human urothelial cells obtained by different methods. In particular, transcripts of CYP1B1 and CYP4B1 are present, coding for enzymes which are active in the metabolism of polycyclic aromatic hydrocarbons and arylamines, respectively.
Keywords: Cytochrome P450; Cell culture; Urothelial cells; CYP expressions; CYP1B1; CYP4B1; CYP2E1
Expression of cytochrome P450 enzymes CYP1A1, CYP1B1, CYP2E1 and CYP4B1 in cultured transitional cells from specimens of the human urinary tract and from urinary sediments by P. H. Roos; R. Belik; W. Föllmann; G. H. Degen; H. J. Knopf; H. M. Bolt; K. Golka (pp. 45-52).
Expression of cytochromes P450 CYP1A1, CYP1B1, CYP2E1 and CYP4B1 was analysed on the transcript level in human urothelial cells obtained by various methods. As a source of urothelial cells, exfoliated cells in urine samples were used. Their expression profiles were determined either immediately after centrifugal enrichment (n=4) or after their cultivation and propagation (n=8). Another source of urothelial cells were ureter specimens from surgical subjects (n=4). Generally, expression was most prominent for CYP1B1 and CYP4B1 among the CYP transcripts analysed. CYP1B1 mRNA was detected in all samples investigated except for one ureter specimen. CYP4B1 mRNA was present in cell cultures from three out of eight healthy subjects, in three out of four directly investigated urinary sediments and in the cells of all five ureter specimens of four donors investigated after resection and subsequent cell culture. In most cases, CYP2E1 transcript levels were lower than those of CYP1B1 and CYP4B1. CYP2E1 mRNA was detected in cell cultures of six out of eight healthy subjects, in one out of four urinary sediments and in three out of five ureter specimens. CYP1A1 mRNA was clearly observed only in cells from resected ureters. In cell cultures the relative mRNA expression levels varied with subjects interindividually, intraindividually and also during the time of cell culture. The study demonstrates constitutive mRNA expressions of xenobiotic metabolising CYP enzymes in human urothelial cells obtained by different methods. In particular, transcripts of CYP1B1 and CYP4B1 are present, coding for enzymes which are active in the metabolism of polycyclic aromatic hydrocarbons and arylamines, respectively.
Keywords: Cytochrome P450; Cell culture; Urothelial cells; CYP expressions; CYP1B1; CYP4B1; CYP2E1
Pulmonary exposure to diesel exhaust particles induce airway inflammation and cytokine expression in NC/Nga mice
by Ken-ichiro Inoue; Hirohisa Takano; Rie Yanagisawa; Takamichi Ichinose; Akinori Shimada; Toshikazu Yoshikawa (pp. 53-53).
Pulmonary exposure to diesel exhaust particles induce airway inflammation and cytokine expression in NC/Nga mice
by Ken-ichiro Inoue; Hirohisa Takano; Rie Yanagisawa; Takamichi Ichinose; Akinori Shimada; Toshikazu Yoshikawa (pp. 53-53).