Molecular toxicology (Mol Toxicol)

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Other titles Molecular toxicology
ISSN 0883-9492
OCLC 12269618
Material type Periodical
Document type Journal / Magazine / Newspaper

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The gene for the rat GST Ya subunit has been examined in detail as a model for understanding the molecular mechanisms of inducibility by xenobiotics and their tissue-specific regulation. The focus of this article is to describe our current understanding of these mechanisms. The discussion will begin with the classification of the types of inducing agents. These pioneering studies suggested that there were multiple mechanisms for the inducibility of GSTs. In fact, the analysis of GST Ya gene expression has identified two different upstream activating elements and putative protein factors through which different classes of inducers act. Finally, the position-specific and tissue-specific regulation of the GST Ya gene will be discussed.
    Molecular toxicology 01/1992; 2(4):215-35.
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    ABSTRACT: The male hybrid B6C3F1 mouse exhibits a 30% spontaneous hepatoma incidence, whereas the paternal C3H/He strain and the maternal C57BL/6 strain exhibit a 60% and a negligible incidence, respectively. In addition, both male and female B6C3F1 mice are extremely sensitive to chemical induction of hepatocarcinogenesis. The Ha-ras, Ki-ras, and myc oncogenes have been implicated in a variety of solid tumors. Specifically, Ha- and, less frequently, Ki-ras have been reported to be activated in B6C3F1 mouse liver tumors. The objective of this study was to examine a possible point of transcriptional control of Ha-ras, Ki-ras, and myc in all three mouse strains, our hypothesis being that these oncogenes may be primed for expression in the nascent liver of those strains exhibiting a high spontaneous hepatoma incidence. A positive correlation has been established between gene expression and the presence of DNAase I hypersensitive sites. DNase I hypersensitive sites were observed in the Ha-ras and myc oncogenes in the three mouse strains. However, Ha-ras appears to possess an additional site in B6C3F1 and C3H/He as compared to C57BL/6. Similarly, the Ki-ras oncogene exhibited a DNase I hypersensitive site only in B6C3F1 and C3H/He mouse liver. These results indicate that the hepatoma-prone strains (B6C3F1 and C3H/He) may have a greater potential for Ha- and Ki-ras expression than does the non-hepatoma-prone strain (C57BL/6).
    Molecular toxicology 11/1991; 2(3):187-97. DOI:10.1080/15287399109531575
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    ABSTRACT: The male hybrid B6C3F1 mouse exhibits a 30% spontaneous hepatoma incidence, and both males and females of this strain are sensitive to chemical induction of liver tumors. The Ha-ras, Ki-ras, and myc oncogenes have been implicated in a variety of solid tumors. Specifically, Ha- and, less frequently Ki-ras have been reported to be activated in B6C3F1 mouse liver tumors, and such activated oncogenes frequently contain a particular point mutation. In light of indications that the transforming capacity of some oncogenes is directly related to the level of the gene product, we hypothesized that transcriptional control of Ha-ras, Ki-ras, and myc is compromised in B6C3F1 mouse liver tumors. A positive correlation has been established between gene expression and hypomethylation. Therefore, the methylation states of these genes were examined in spontaneous liver tumors and in tumors induced by two diverse hepatocarcinogens: phenobarbital and chloroform. Ha-ras was found to be hypomethylated in all tumors examined, whereas Ki-ras was sometimes hypomethylated; such hypomethylation might play a role in the promotion stage of carcinogenesis. The methylation state of myc was unaltered, although this gene appeared to be amplified in tumors. These results suggest that a component of the mechanism by which these oncogenes are activated in B6C3F1 mouse liver tumors involves loss of stringent control of expression, via hypomethylation of the ras oncogenes and, possibly, amplification of myc. These results support the assertion that tumors induced by different classes of carcinogens or arising spontaneously share common biochemical pathways of oncogene activation during tumorigenesis.
    Molecular toxicology 11/1991; 2(2):99-116. DOI:10.1080/15287399109531574
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    ABSTRACT: Sister chromatid exchanges (SCE) have been examined in human lymphocytes following in vitro treatments with metal salts, nickel sulfate, lead sulfate and sodium arsenite. All of the metal salts produced significant increases in the SCE frequencies over the levels for untreated lymphocytes. The SCE frequencies were also examined for metal treatments combined with ultraviolet light (200 ergs/mm2). For the lead treatments combined with the UV dose selected, an additive SCE response was observed compared to the SCE responses for UV or metal alone. The nickel and arsenite treatments combined with UV produced a less than additive SCE response for most concentrations tested. These results suggest that nickel or arsenite present in complex mixtures may reduce the SCE response to other compounds in the mixture normally capable of producing a much stronger SCE response and therefore lead to an underestimate of the effects of chemical exposure.
    Molecular toxicology 04/1989; 2(2):129-36.
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    ABSTRACT: We have previously demonstrated that a number of metal salts have the capacity to inhibit the DNA repair process in human cells. In order to determine a role for non-protein thiols (TNPT) in this inhibition, we investigated repair of X-ray damage in metal-treated HeLa cells under normal conditions and conditions in which cellular thiols had been depleted by treatment with buthionine sulfoximine (BSO) and diethyl maleate (DEM). The combination reduced cellular TNPT by 92%, and cells so depleted became sensitized to X-ray-induced killing and exhibited retarded sealing of X-ray-induced DNA single-strand breaks. Thiol depletion also sensitized cells to the cytotoxicity of certain but not all metals tested. The sensitivity to copper was increased over 6000-fold, and significant enhancement of killing was also seen in cells treated with arsenic, lead, and mercury. Smaller effects were observed with cadmium and nickel, and sensitivity to manganese, magnesium, cobalt or zinc was not substantially altered. Enhanced sensitivity to X-ray killing was found in cells treated with nickel, cadmium, zinc, arsenic, and copper under conditions in which thiols were not limiting. In thiol-depleted cells, sensitivity was not further increased in the case of nickel and arsenic but at least additively affected for copper, mercury and zinc. X-Ray-induced single-strand break repair was retarded by treatment of cells with mercury, nickel, zinc, arsenic, and copper in thiol-normal cells. In thiol-depleted cells, repair inhibition by zinc, arsenic, and copper was nearly complete, while little additional effect on repair was seen following mercury and nickel treatment. An examination of the effects of brief metal treatment on cellular TNPT revealed that copper strongly decreased thiol levels whereas the other metals tested either had no effect on TNPT or reduced TNPT levels to no less than 48% under the conditions employed. No simple relationship appears to exist relating loss of cellular thiols and sensitivity of repair in the series of metals tested. Clear, although indirect, evidence exists, however, that sensitivity to X-rays is mediated through thiols and that the interaction of metals and thiols in the cell may be an important factor in modulating the response to irradiation.
    Molecular toxicology 04/1989; 2(2):117-28.
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    ABSTRACT: Among the indicators of membrane damage, the leakage of intracellular components into the medium is the most directly related to the perturbations of the membrane molecular organization. The extent of the damage can be evaluated from the size of the released components. We have designed a protocol for the detection of membrane leakage based on the preincubation of cells with tritiated adenine for 24 h, followed by a 24-h chase in nonradioactive medium. The treatment takes place when the distribution of the precursor among its end products has reached the plateau, and thus the differences of radioactivity in the fractions obtained from the control and treated cultures (medium, nucleotide pool, RNA, DNA) correspond to actual quantitative variations induced by the test chemical. Aliquots of the medium are processed to determine which percentage of the released material is macromolecular, in order to distinguish between mild and severe membrane damage. The origin of the extracellular radioactivity can be recognized from the variations of RNA counts in the treated cells. DNA radioactivity is used to evaluate the number of cells that remain attached to the plates in the different conditions of treatment. By this means, generalized permeabilization of membranes to macromolecules is distinguished from complete solubilization of only a subpopulation of cells. We present some examples of application of the protocol with detergents (LAS, SDS, Triton X-100) and with Cr(VI), which damages cell membranes by a different mechanism of action.
    Molecular toxicology 02/1989; 2(1):27-38.
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    ABSTRACT: We provide evidence for two new classes of halogenated aromatic hydrocarbon ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or Ah) receptor: brominated naphthalenes and iodobenzenes. Polybrominated naphthalenes with four or more bromine atoms concentrated in lateral positions were shown to bind specifically and with high affinity (Kd approximately 10(-8) M) to the Ah receptor in rat liver cytosol preparations. The hexabrominated naphthalene isomers bind with high and nearly equal affinities but have been previously shown to have different toxicological properties. Possible explanations for these differences include differences in metabolism, antagonist versus agonist Ah receptor binding of some isomers, and the involvement of other binding sites in vivo that require different structural requirements. The moderate binding activity of the diiodobenzenes suggests that thyroid hormones should receive further study as possible endogenous ligands for the Ah receptor. It is difficult to explain the binding results with these two classes of compounds using previously developed molecular concepts for Ah receptor interactions based primarily on molecular size considerations.
    Molecular toxicology 02/1989; 2(1):39-52.
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    ABSTRACT: We have previously shown that the inhibition of MNU-induced DNA repair by arsenite occurs after the incision step in Chinese hamster V79 cells. We now report that nuclear DNA ligase activity is inhibited after arsenite treatment and that the inhibited activity is mostly DNA ligase II. Both constitutive and MNU-inducible levels of DNA ligase II are inhibited. The addition of arsenite in vitro also indicates that DNA ligase II is more sensitive to arsenite inhibition than DNA ligase I. Since DNA ligase II is reported to be involved in the ligation step of excision repair, its inhibition by arsenite is a likely mechanism for the inhibition of DNA repair by arsenite and may account for the fact that arsenite acts as a comutagen with a number of different types of mutagens. The carcinogenicity of arsenite may also be a result of ligase inhibition.
    Molecular toxicology 02/1989; 2(1):1-9.
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    ABSTRACT: The mutagenicity of a series of 19 aromatic amines had been previously measured in Salmonella typhimurium strains TA98 (frame-shift) and TA100 (base-pair) with the addition of S9 from Aroclor 1254-induced rat liver. A quantitative structure-activity relation (QSAR) study using multiple regression analysis points out the influence of three factors on mutagenicity: lipophilic character, position of the amine group, and whether it is free or acetylated, as expressed by log P and two indicator variables I1 and I2, respectively. The multiple regression equations explain 78 and 88% of the variance in log mutagenicity in TA98 and TA100, respectively. First of all, mutagenicity was shown to increase with lipophilicity. On the other hand, mutagenicity is reduced when the amine or acetamido position is ortho to the juncture because of steric hindrance in its biotransformation compared with a non-ortho isomer. It is decreased also by the acetylation of the amine group, probably because the acetyl group needs to be first split off prior to oxidation of the amine group to -NHOH.
    Molecular toxicology 02/1989; 2(1):53-65.
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    ABSTRACT: The proteins cross-linked to the DNA of cultured Chinese hamster ovary cells after exposure to cis-diamminedichloroplatinum(II) (cis-Pt), chromate, and formaldehyde were compared by two-dimensional (2D) gel electrophoresis, immunoblotting, and centrifugal assays that measured cross-link stability. Chromate and cis-Pt cross-linked seven of the same nonhistone proteins, such as actin, to DNA. In contrast, formaldehyde selectively formed histone-DNA cross-links. Immunoblotting experiments showed that all three chemicals cross-linked a 97-kDa nuclear protein to the DNA despite their different chemical reactivity with DNA and proteins. The chromate- and cis-Pt-induced cross-links were disrupted by thiourea, 2-mercaptoethanol, and EDTA, indicating that the metal could be chemically displaced from the cross-links. The formaldehyde-induced complexes required degradation with DNase 1 for the resolution of histones on 2D gels and were not chemically labile like the metal-induced cross-links. The agents and methodology used here could be applied to the study of additional nuclear proteins that bind or reside near the DNA.
    Molecular toxicology 02/1989; 2(1):11-26.
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    ABSTRACT: TCDD administered to NIH 3T3 fibroblast cells transfected with a plasmid containing MMTV-LTR and mouse ras DNAs caused an increased level of p21ras protein and down-regulation of EGF receptor. This effect occurred only in the cells with introduced N-ras or Ha-ras under transcriptional control of glucocorticoid-sensitive MMTV-LTR but not ones without these DNAs. The MMTV-LTR ras-incorporated cells treated with either dexamethasone or TCDD grew in soft agar to form colonies (anchorage independent growth), while nontreated cells did not, indicating profound cellular changes due to activation of N-ras by these two agents.
    Molecular toxicology 01/1989; 2(3):177-86.
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    ABSTRACT: Four new peaks were observed upon amino acid analysis of alpha 1-proteinase inhibitor (alpha 1-PI), which was inactivated by acrolein under in vitro conditions. The first peak emerged just before ammonia, the second and third between ammonia and lysine, and the fourth between histidine and arginine. The new fourth peak was also observed when model compounds of lysine (N-acetyllysine or polylysine) were reacted with acrolein and subsequently processed for amino acid analysis. This new compound was purified by high-voltage paper electrophoresis and subjected to fast atom bombardment mass spectrometry, which showed a protonated molecule ion at m/z 203 [M + H]+ followed by m/z 186 [M + H+ - NH3]+. This compound was thus identified as 3-oxopropyllysine, a lysine adduct of acrolein. Similarly, when a model polypeptide of histidine, polyhistidine, was reacted with acrolein under the same conditions as alpha 1-PI, three new peaks (besides histidine) emerged from the column. Their elution times corresponded to the first three new peaks found in the hydrolysates of acrolein treated alpha 1-PI.
    Molecular toxicology 01/1989; 2(3):137-45.
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    ABSTRACT: Pretreatment of mammalian cell with DNA-damaging agents, such as UV light or mitomycin C, but not the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA), results in the enhanced repair of subsequently transfected UV-damaged expression vectors. To determine the cellular factors that are responsible for this enhancement, we have used a modified gel retardation assay to detect the proteins that interact with damaged DNA. We have identified a constitutive DNA binding protein in extracts from primate cells that has a high affinity for UV-irradiated double-stranded DNA. Cells pretreated with UV light, mitomycin C, or aphidicolin, but not TPA or serum starvation, have higher levels of this damage-specific DNA binding (DDB) protein. These results suggest that the signal for induction of DDB protein can either be damage to the DNA or interference with cellular DNA replication. The induction of DDB protein varies among primate cells with different phenotypes: (1) virus-transformed repair-proficient cells have partially or fully lost the ability to induce DDB protein above constitutive levels; (2) primary cells from repair-deficient xeroderma pigmentosum (XP) group C, and transformed XP groups A and D, show constitutive DDB protein, but do not show induced levels of this protein 48 h after UV; and (3) primary and transformed repair-deficient cells from one XP E patient are lacking both the constitutive and the induced DDB activity. The correlation between the induction of the DDB protein and the enhanced repair of UV-damaged expression vectors implies the involvement of the DDB protein in this inducible cellular response.
    Molecular toxicology 01/1989; 2(4):255-70.
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    ABSTRACT: Validation in the context of in vitro toxicity tests is defined, and various aspects of the validation process are discussed, including the design and conduct of interlaboratory validation schemes; the selection of tests, participating laboratories, and test chemicals; the selection and use of in vivo data; in vivo/in vitro data comparison; the question of "false" results; in vitro cytotoxicity as a predictor of actual lethal toxicity; and the validation of alternatives to the Draize eye irritancy tests. It is concluded that a thorough reevaluation of current practice is essential if the promise and potential of nonanimal toxicity tests are to be fully realized and if valid alternative tests acceptable to regulatory agencies are to be developed.
    Molecular toxicology 01/1989; 1(4):547-59.
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    ABSTRACT: In vitro assessment of the efficacy/capacity of toxicants (e.g., cancer chemotherapeutic agents, environmental pollutants, etc.) to damage/kill cells and/or inhibit growth (cell duplication) requires accurate measurement of target cell viability as a function of exposure. Rapid measurement of viability, such as can be achieved employing fluorescent probes of metabolic function in combination with instrumental analysis, is highly desirable. However, we observe that exposure to chemicals (of unrelated type) complicates the interpretation of viability data and, in the case of perturbed cells, questions the validity of viability growth assays based on intrinsic enzyme activity. Viability commonly is determined flow cytometrically (FCM) by the carboxyfluorescein diacetate (CFDA)/propidium iodide (PI) assay. Nonfluorescent CFDA is taken up by diffusion and converted via cytoplasmic esterase-catalyzed hydrolysis to carboxyfluorescein (CF), a negatively charged fluorescent molecule that is retained (incompletely) by the cell. As such, if CF fluorescence intensity is a relative measure of enzyme activity, it also can be considered an index of cellular vigor (metabolic rate). It is generally accepted that the viable cell excludes both basic dyes, such as PI, and acidic dyes, such as trypan blue, and uptake is indicative of irreversible cellular injury presaging cell death. We observe that, following incubation for 4 h with 0.5-1.0 microM tributyltin (TBT), a potent environmental toxicant, murine erythroleukemic cells (MELC) exhibit enhanced (supranormal) CF fluorescence compared to control cells. Apparent cell volume (ACV) is unaltered, and because such cells exclude PI, they are considered viable in terms of the CFDA/PI assay. However, rate of growth (increase in cell number over 48 h) is depressed, suggesting that supranormal CF fluorescence, even in the absence of PI uptake, is indicative of cellular perturbation. In effect, although CF fluorescence is the product of an enzyme-catalyzed reaction and, therefore, an indicator of vital function (enzyme activity), it apparently is not a reliable index of cellular vigor. At higher TBT concentrations (greater than 1.0, but less than 50.0 microM), the cells exhibit both increased CF fluorescence and PI fluorescence and are growth inhibited. MELC exposed to the cancer chemotherapeutic agents adriamycin, m-AMSA, or crisnatol (Burroughs Wellcome 770U82) also exhibit increased cellular CF fluorescence. However, rate of growth is decreased and ACV increased. The latter, measured either as a function of electrical resistance (Coulter volume) or by the FCM parameter axial light loss could account for the increase in mean CF fluorescence.(ABSTRACT TRUNCATED AT 400 WORDS)
    Molecular toxicology 01/1989; 2(4):271-84.
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    ABSTRACT: To further understand the molecular nature of changes leading to chemically induced ouabain resistance in C3H/10T1/2 Cl 8 (10T1/2) cells, we isolated plasma membranes from wild-type and ouabain-resistant (Ouar) 10T1/2 cells and characterized (Na,K)-ATPase activity in the plasma membrane fraction. (Na+,K+)-ATPase enzyme activity in membrane fractions extracted from wild-type 10T1/2 cells was inhibited in a concentration-dependent manner by ouabain and was completely inhibited by 2.4 mM ouabain. Lineweaver-Burke and Eisenthal/Cornish-Bowden analysis indicated that the inhibition was uncompetitive. Ten to 45% of (Na+,K+)-ATPase enzyme activity extracted from three Ouar 10T1/2 cell lines cultured in 1 mM ouabain was resistant to 2.4 mM ouabain, depending on the cell line. Resistance of (Na+,K+)-ATPase activity in the plasma membrane fraction of Ouar cells to inhibition by ouabain and resistance of cultured Ouar cells to the cytotoxicity of ouabain occurred over similar concentrations of ouabain (0.1-3mM). Two ouabain-resistant cell lines, Ouar MNNG Cl 2 and Ouar MCA Cl 16-7, demonstrated the same total (Na+,K+)-ATPase specific activity as 10T1/2 cells, but the fraction of Ouar enzyme activity increased (from 18 to 40% in MNNG Cl 2 cells and from 10 to 25% in Sp Ouar Cl 16 cells) when the cells were cultured in ouabain. Thermal denaturation profiles and pH dependence profiles of (Na+,K+)-ATPase activity in plasma membranes from wild-type and Ouar 10T1/2 cells were identical. A 3.9-kb (Na,K)-ATPase alpha subunit mRNA transcript was found in 10T1/2 cells, and in the Ouar MNNG Cl 2 cell line cultured in the presence or absence of ouabain. There was no amplification of the gene coding for the alpha subunit of (Na+,K+)-ATPase in the chemically induced Ouar MNNG Cl 2 cell line, whether this cell line was cultured in the presence or absence of ouabain. These studies provide further evidence that the Ouar phenotype of chemically induced and spontaneous Ouar 10T1/2 cell lines derives from Ouar (Na+,K+)-ATPase activity, and that this Ouar (Na+,K+)-ATPase activity increases further in some cell lines cultured in the presence of ouabain.
    Molecular toxicology 01/1989; 2(2):75-98.
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    ABSTRACT: The effects of adaptation of normal rat kidney cells (NRK 52-E) to growth in 5 or 10 microM lead nitrate on the rates of DNA synthesis and on the rate and pattern of protein synthesis was studied. The rate of [3H]thymidine incorporation into DNA was increased in normal cells, but remained unchanged in one lead-adapted cell line (only 5 microM NRK studied). Increased rates of [3H]leucine incorporation into nonadapted NRK cells were found only at times up to 3 h; in contrast, the lead-adapted cells showed such increases only at longer times. The most pronounced differences between normal and lead-adapted cells were found with lead concentrations of 10 or 50 microM lead nitrate. Lead-adapted control cells incorporated 170% of the [3H]leucine taken up by nonadapted cells. In both adapted and nonadapted cells the pattern of synthesis of specific proteins showed varied and dose-dependent differences between the three cell sublines examined. The changed sensitivity of both DNA and protein synthesis following lead exposure appears to be a potent parameter in the development of resistance, perhaps through the development of specific lead-binding proteins.
    Molecular toxicology 01/1989; 2(3):163-75.
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    ABSTRACT: The present study was undertaken to isolate and identify various lipids bound to 14C label during hepatic microsomal metabolism of 14CCl4 in vitro under anaerobic conditions and in vivo in rats. The two major radioactive fractions identified by thin-layer chromatography each for neutral lipids and phospholipids from in vitro and in vivo experiments corresponded to fatty acids and triglycerides and to phosphatidylcholine (PC) and phosphatidylethanolamine (PE), respectively. Approximately 89% of the radioactivity associated with phospholipids was found in PC and PE fractions. Hydrolysis of PC and PE with phospholipase A2 (EC released about 50% of the total radioactivity as lipid moieties corresponding to fatty acids. The radioactive neutral lipids and the lipid moieties hydrolyzed from PC and PE were methylated with boron trifluoride in methanol. These methylated lipids were separated by reversed-phase high-performance liquid chromatography (HPLC), and the elution profiles of 14C label found for the lipids obtained from in vitro experiments were similar to those from in vivo. The major radioactive fractions eluted immediately after methyl oleate were identified as trichloromethyloctadecenoic and trichloromethyleicosatrienoic acid methyl esters by chemical ionization mass spectrometry. The mass spectral analysis of these fractions also indicated the formation of dichlorocarbene adduct of oleic acid. However, similar mass spectrometric detection of trichloromethylated lipids was not evident in neutral lipids and phospholipids isolated from in vivo studies. The 14C-labeled lipids eluted as a nonpolar fraction exhibited a high molecular weight containing more than three chlorines. Dimerization and cross-linking of trichloromethylated lipids based on HPLC and mass spectral analysis are also discussed in this paper.
    Molecular toxicology 01/1989; 2(3):199-213.

  • Molecular toxicology 01/1989; 2(3):147-50.
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    ABSTRACT: The inducibility of metallothionein by cis- and trans-diamminedichloroplatinum(II) and their hydrolyzed products was studied in the JAr (a human choriocarcinoma) cell line. The metallothionein present in the cytosolic fraction of these cells was measured after a 12- or 24-h exposure to a fresh metal solution or a solution that had been allowed to hydrolyze. These results demonstrate that hydrolysis of the cis isomer produces a species that is able to give a 374% increase in the cytosolic level of metallothionein after a 24-h exposure to 40 microM of the metal. Fresh cisplatin, on the other hand, gives a maximal increase of 118% under the same conditions. Transplatin and its hydrolyzed species did not induce metallothionein. These results may indicate that hydrolysis of cisplatin performs an important role in the metabolism and possibly the toxicity of this widely used agent for cancer chemotherapy.
    Molecular toxicology 01/1989; 2(2):67-74.