PubMed Health⌕ Search

Biomedical subjects

A Hartwig

Publications and source records attributed to A Hartwig.

At least 19 recordsLinked to original sources
PubMed1995

Current aspects in metal genotoxicity.

While carcinogenic metal ions are mostly non-mutagenic in bacteria, different types of cellular damage have been observed in mammalian cells, which may account for their carcinogenic potential. Two modes of action seem to be predominant: the induction of oxidative DNA damage, best established for chromium compounds, and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA damaging agents. In the case of Cd(II), Ni(II), Co(II), Pb(II) and As(III), DNA repair processes are disturbed at low, non-cytotoxic concentrations of the respective metal compounds. Even though different steps in DNA repair are affected by the diverse metals, one common mechanism might be the competition with essential metal ions.

Animals↗
PubMed1995

Sensitive nonradioactive detection of UV-induced cyclobutane pyrimidine dimers in intact mammalian cells.

In this paper we present a sensitive procedure to determine specifically the induction as well as the removal of cyclobutane pyrimidine dimers in intact mammalian cells without radioactive labeling of the DNA. This technique allows the detection of DNA damage by UV doses as low as 0.1 J/m2. The method consists of gentle lysis of cell monolayers, high-salt treatment and incubation with the cyclobutane pyrimidine dimer-specific repair enzyme T4 endonuclease V, followed by alkaline unwinding, hydroxyapatite chromatography and fluorimetric DNA analysis. The number of T4 endonuclease V-sensitive sites correlates well with the amount of UV-induced cyclobutane pyrimidine dimers reported in the literature, indicating that these cyclobutane pyrimidine dimers are recognized quantitatively by the system. The assay is easily transferable to the detection of other types of DNA adducts by applying different damage-specific repair enzymes, providing a sensitive method to investigate the induction and the repair of DNA lesions without the use of radioactive labeling.

Alkalies↗
PubMed1995

Case of bilateral non-Hodgkin's lymphoma after dental extractions in a patient with the human immunodeficiency virus.

It has long been known that immunocompromised patients have an increased risk of getting malignant neoplasms, with lymphomas predominating. This increase in lymphomas is especially notable in the population infected with the human immunodeficiency virus (HIV). Before the outbreak of the human immunodeficiency virus these neoplasms rarely occurred in the maxillofacial region; they are now being seen with a greater frequency. This report details a case of bilateral non-Hodgkin's lymphoma that was initially misdiagnosed as an odontogenic infection.

Adult↗
PubMed1994

Nickel(II) interferes with the incision step in nucleotide excision repair in mammalian cells.

Nickel compounds are carcinogenic to humans and experimental animals. However, the mechanisms leading to tumor formation are still not understood since the mutagenic potential is rather weak. In contrast, nickel(II) enhances the cytotoxicity and genotoxicity in combination with several other DNA-damaging agents. To elucidate possible interactions with DNA repair processes, the effect of nickel(II) on the nucleotide excision repair pathway has been investigated after UV irradiation in HeLa cells. Nickel(II) blocks the removal of cyclobutane pyrimidine dimers as determined by T4 endonuclease V-sensitive sites. When the alkaline unwinding technique was applied, significantly less transient DNA strand breaks after UV irradiation were detected in the presence of nickel(II) compared to UV alone, suggesting an inhibition of the incision step of nucleotide excision repair. Once incisions are made, the ligation of repair patches is delayed as well in nickel-treated cells, as observed by the alkaline unwinding and nucleoid sedimentation techniques. This inhibition of DNA repair is partly reversible by the addition of magnesium(II), indicating that the competition between Ni2+ and Mg2+ may provide an important mechanism for the disturbance of DNA-protein interactions involved in the repair process. Since the repair inhibition is observed at noncytotoxic concentrations of nickel(II), it may well be relevant for its carcinogenic action.

Colony-Forming Units Assay↗
PubMed1994

Mechanisms in nickel genotoxicity: the significance of interactions with DNA repair.

Even though nickel compounds are strong carcinogens, the underlying mechanism is still unclear. In contrast to their weak mutagenic potential, they enhance the cytotoxicity and genotoxicity of UV light, X-rays and cytostatic agents like cis-platinum, trans-platinum and mitomycin C. Studies in combination with UV light indicate an inhibition of DNA repair, presumably at the incision step of nucleotide excision repair. Possible reasons for repair inhibition are structural changes of the DNA or direct interactions with repair enzymes or proteins, possibly by competition with essential metal ions.

Animals↗
PubMed1994

Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: a review.

Compounds of lead and cadmium have been shown to be carcinogenic to humans and experimental animals. However, the underlying mechanisms are still not understood. In mammalian cells in culture, lead(II) is weakly mutagenic after long incubation times and generates DNA strand breaks only after treatment with high, toxic doses. Cadmium(II) induces DNA strand breaks and chromosomal aberrations, but its mutagenic potential is rather weak. However, both metals exert pronounced indirect genotoxic effects. Lead(II) is comutagenic towards UV and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and enhances the number of UV-induced sister chromatid exchanges in V79 Chinese hamster cells. With regard to DNA repair, lead(II) causes an accumulation of DNA strand breaks after UV-irradiation in HeLa cells, indicating an interference with the polymerization or ligation step in excision repair. Cadmium(II) enhances the mutagenicity of UV light in V79 Chinese hamster cells and an increased sensitivity toward UV light is observed in various rodent and human cell lines. Furthermore, an inhibition of unscheduled DNA synthesis after UV-irradiation and a partial inhibition of the removal of UV-induced DNA lesions has been shown. For both metals, the indirect genotoxic effects are observed at low, nontoxic concentrations, suggesting that an interference with DNA repair processes may be predominant at biologically relevant concentrations. This might also explain the conflicting results of epidemiological studies obtained for both metals. Possible mechanisms of repair inhibition are discussed.

Animals↗
PubMed1992

Mechanisms of cobalt(II) uptake into V79 Chinese hamster cells.

V79 Chinese hamster cells were used as a model for the characterization of the Co(II) uptake into mammalian cells as well as the mechanisms involved. Co(II) was taken up in a dose and time dependent manner. The uptake was exponential without saturation in the tested concentration range up to 400 microM CoCl2. Furthermore, there was a high intracellular cobalt accumulation at elevated extracellular Co(II) doses (up to 16 fold at 200 microM). The time course of Co(II) uptake showed a maximum after about 8-12 h with no further change after the longest tested incubation time (24 h). The uptake of Co(II) into V79 cells seems to be mediated by multiple mechanisms: active, energy consuming transport like ion pumps and endocytosis, since the Co(II) uptake was significantly reduced by ouabain (an inhibitor of the Na+/K+ATPase), N-ethylmaleinimide (an inhibitor of the Ca2+/Mg2+ATPase and the Na+/K+ATPase), chlorpromazine (a calmodulin antagonist and inhibitor of the Ca2+/Mg2+ ATPase) as well as by the endocytosis inhibitor chloroquine. Furthermore, the two agents iodoacetate and potassium cyanide, which produce ATP depletion, resulted in a diminution of the intracellular cobalt concentration. An uptake through anion channels could be excluded, since 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid was not inhibitory.

Animals↗
PubMed1992

The genetic toxicology of cobalt.

Genetic and related effects of cobalt compounds are reviewed and discussed with respect to mechanisms. In prokaryotic assays, Co(II) salts generally are nonmutagenic. In Saccharomyces cerevisiae, CoCl2 is mutagenic to mitochondrial genes and weakly mutagenic or nonmutagenic to chromosomal genes. In plants, Co(II) salts induced gene mutations and chromosomal aberrations. In mammalian cells in vitro, Co(II) compounds caused DNA strand breaks, sister-chromatid exchanges and aneuploidy, but not chromosomal aberrations. In two cell lines, CoCl2 was weakly mutagenic. Interestingly, the poorly soluble compound CoS caused DNA strand breaks and morphological transformation of mammalian cell lines. In contrast to its weak clastogenic and mutagenic properties, cobalt(II) exerts pronounced antimutagenicity in bacteria and mostly comutagenic effects in mammalian cells. In Escherichia coli CoCl2 lowered the frequency of mutations induced by MNNG, uv or X rays. In Chinese hamster V79 cells, CoCl2 enhanced the mutagenicity and clastogenicity of uv light but not of gamma rays. Regarding direct genotoxic mechanisms, Co(II) induces the formation of reactive oxygen species when combined with hydrogen peroxide in cell-free systems. At high (i.e., millimolar) concentrations, Co(II) also decreases the fidelity of DNA synthesis. Regarding anti- and co-mutagenic mechanisms, evidence for the interference of Co(II) with DNA repair processes is discussed. These mechanisms are regarded as relevant for the risk assessment of human exposure to cobalt in combination with other agents.

Animals↗
PubMed1991

Modulation by Co(II) of UV-induced DNA repair, mutagenesis and sister-chromatid exchanges in mammalian cells.

In bacterial test systems, Co(II) has been shown to be antimutagenic in combination with several chemical and physical agents. To investigate whether such modulations also apply to mammalian cells, the effect of Co(II) on UV-induced mutagenesis, sister-chromatid exchanges as well as DNA damage and its removal was determined. Co(II) itself is weakly mutagenic at the HPRT locus and increases the frequency of sister-chromatid exchanges. Additionally, at both endpoints the metal ions enhance the genotoxicity of UV light. To discriminate between an enhancement of DNA damage and an interference with repair processes, the number of pyrimidine cyclobutane dimers was determined by HPLC. While the induction of these DNA lesions is not affected by Co(II), their removal is inhibited at concentrations of 75 microM Co(II) and higher. Analysis of the kinetics of strand-break induction and closure after UV irradiation by nucleoid sedimentation reveals an accumulation of strand breaks in the presence of Co(II). This indicates that either the polymerization or the ligation step in excision repair is affected. Since similar interactions with the processing of UV-induced DNA damage have been observed with other carcinogenic and/or mutagenic metal ions, this appears to be a common mechanism of metal genotoxicity.

Animals↗
PubMed1990

Indirect mechanism of lead-induced genotoxicity in cultured mammalian cells.

The data concerning the mutagenic, clastogenic and carcinogenic properties of inorganic lead compounds have been conflicting. To investigate whether the genotoxicity of lead is due to indirect effects such as interference with DNA-repair processes, the induction of mutations, sister-chromatid exchanges and strand breaks by lead ions alone as well as in combination with UV light as a standard mutagen were determined. Lead acetate alone does not induce DNA-strand breaks in HeLa cells or mutations at the HPRT locus and sister-chromatid exchanges in V79 Chinese hamster cells. However, at all endpoints tested, lead ions interfere with the processing of UV-induced DNA damage. They inhibit the closing of DNA-strand breaks after UV irradiation and enhance the number of UV-induced mutations and sister-chromatid exchanges, indicating an inhibition of DNA repair. These data point out the necessity to consider such indirect effects when assessing the genotoxicity of metal compounds. As possible mechanisms of repair inhibition we suggest either the interaction with repair enzymes such as polymerase or ligase or else the interaction with calcium-regulated processes, for example with calmodulin.

Animals↗
PubMed1990

The Carolina Nosology of Destructive Behavior (CNDB).

This article sets forth a multiaxial system for cataloging individuals who manifest destructive behavior toward themselves, others, or property. An initial codification to describe the characteristics of the destructive behavior of the individual is presented, followed by a description of a quaternary axial system which catalogs in a clinically relevant manner, individuals engaging in destructive behavior. The four axes presented and developed are Axis A--a medical diagnosis axis, Axis B--an axis of psychological correlates, Axis C--an axis of biological correlates, and Axis D--an axis of moral/cultural correlates. This nosology is proposed in order to standardize the coding of human destructive behavior. It is intended to be used by members of the clinical and research communities in order to compare patient types and their relationship to treatment interventions.

Aggression↗
PubMed1990

Ethical issues in selecting patients for treatment with clozapine: a commentary.

Three ethical constructs of distributive justice--utilitarianism, Marxism, and the theories of John Rawls--are applied to selection of patients for treatment with clozapine. Elements of an ethical selection process include a means of monitoring the clinical effectiveness of the drug so that it is not wasted and procedures for ensuring that patients' rights to advocacy and due process are met. The authors suggest that a disproportionate number of patients with tardive dyskinesia may receive clozapine because clinicians and hospitals risk litigation if these patients continue to receive standard neuroleptics and experience worsening side effects.

Chronic Disease↗
PubMed1989

Enhancement of UV-induced mutagenesis and sister-chromatid exchanges by nickel ions in V79 cells: evidence for inhibition of DNA repair.

With regard to contradictory results concerning the mutagenicity of nickel compounds in short-term assays, especially in bacterial test systems, Chinese hamster V79 cells were used to measure mutagenicity, comutagenicity and the induction of sister-chromatid exchanges (SCEs) by NiCl2. We confirmed the induction of mutations at the HGPRT locus as well as SCEs. In addition, NiCl2 shows a pronounced comutagenic effect towards UV. When using confluent cultures or resting cells due to serum deprivation, where more time is given for repair processes, the comutagenic effect is higher compared to logarithmically growing cells (10 and 4 times, respectively, compared to twice). Hence, we attribute this enhancement in mutagenicity to inhibition of DNA repair. Also the increase in induced SCEs after combined treatment with UV and NiCl2 supports this thesis. Furthermore, NiCl2 enhances the cyto-toxicity of cis-DDP about 12-fold. Since no comutagenic effect is observed in combination with MMS, we suggest that the inhibition of DNA repair by Ni(II) applies to all DNA changes that are repaired by the 'long-patch' excision repair system. This inhibition may occur via replacement of other divalent metal ions essential in repair and regulation processes.

Cell Line↗
PubMed1988

Genetic toxicology of lead compounds.

We have investigated the activity of insoluble and soluble lead compounds in inducing mutagenesis, cell transformation and sister chromatid exchange in mammalian cells. Insoluble lead sulfide, readily phagocytized, was more than four times as toxic to V79 cells on a microM basis, than two moderately soluble lead compounds although the exposure time for the soluble salts was five times longer. These findings demonstrate the importance of different cellular mechanism(s) of metal uptake and bioavailability. Both insoluble lead sulfide and more soluble lead nitrate were mutagenic at the HPRT locus in V79 cells. Although less mutagenic at the higher concentrations, lead nitrate at a concentration of 500 microM enhanced the mutation frequency greater than 6-fold above background following a 5-day exposure. Although the mechanism(s) by which lead induces mutations is unknown, failure of both compounds to induce SCE and DNA single-strand breaks, detectable by alkaline elution, suggests that lead-induced mutations may not be a result of direct damage to DNA but may occur via indirect mechanisms including disturbances in enzyme functions important in DNA synthesis and/or repair, or in DNA-helical structure. Lead acetate also transformed SHE cells in a dose-response fashion following a 48-h exposure. Our results indicate that lead compounds may be genotoxic by an indirect mechanism, and lend support to the view that lead is a carcinogen.

Animals↗