Lennart Romert

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Thiol-enhanced decomposition of MNNG, ENNG and nitrosociametidine: relationship to mutagenicity in V79 Chinese hamster cells

Carcinogenesis (1991)

Lennart Romert Stellan Swedmark Dag Jenssen

The nitrosated form of cimetidine (Tagamet), nitrosocimetidine (NC), belongs to a group of nitrosoamidines in which the mutagenic and carcinogenic properties of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) have been studied in detail. The common mechanism of action of these compounds is that nucleophilic atoms can attack their iminocarbon, thereby leading to the formation of alkyldiazohydroxide and, subsequently of an alkylating and mutagenic diazonium ion. A competitive, non-mutagenic pathway involves denitrosation, which is strongly dependent on pH and can be enhanced by glutathione transferase. The influence of different thiols (e.g. glutathione and the L- and D-forms of N-acetylcysteine (L-NAC and D-NAC respectively] at different extra- and intracellular concentrations on the mutagenicity of these nitrosoamidines in V79 cells has been studied in the present investigation. The results demonstrate that the mutagenicity of MNNG and ENNG is highly dependent on where their reaction with thiols takes place. Thus, an increase in the intracellular glutathione level in combination with treatment with MNNG (or ENNG) in thiol-free medium elevated the mutagenicity, whereas treatment with thiols in the medium reduced mutagenicity. The mutagenicity of NC was, on the other hand, only slightly affected by increasing extra- or intracellular thiol levels. The dependence of NC-induced mutagenicity on thiols was indicated, however, by the finding that depletion of intracellular glutathione reduced this mutagenicity almost completely. The effects of treatments with thiols alone or in combination with glutathione transferases suggest that, under our assay conditions (e.g. physiological pH and thiol levels, in combination with low levels of the nitrosoamidines), no denitrosation occurs. On the contrary, our results indicate that intracellular thiols, and possibly glutathione transferases, potentiate the production of mutagenic species from these nitrosamidines.

Chinese hamster

Methylnitronitrosoguanidine

Thiol

10.1093/carcin/12.5.847

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Citations (10)

Characterization of xenobiotic metabolism by co-cultivation-mediated mutagenesis

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (1987)

L.-H. Zhang Lennart Romert Dag Jenssen

Xenobiotic

10.1016/0027-5107(87)90143-6

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Citations (0)

Genotoxicity testing of extracts of a Swedish moist oral snuff

Mutation Research/Genetic Toxicology (1991)

Tommy Jansson Lennart Romert Jan Magnusson Dag Jenssen

Clastogen

Ames test

Sister chromatid exchange

Chromosome aberration

Methyl methanesulfonate

10.1016/0165-1218(91)90056-r

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Citations (21)

MEIC Evaluation of Acute Systemic Toxicity

Alternatives to Laboratory Animals (1996)

Cecilia Clemedson Elisabeth McFarlane-Abdulla Marianne Andersson Frank A. Barile Mabel C. Calleja

The multicentre evaluation of in vitro cytotoxicity (MEIC) study is a programme designed to evaluate the relevance of in vitro toxicity tests for predicting human toxicity, and is organised by the Scandinavian Society for Cell Toxicology. The project started in 1989 and is scheduled to be finished by June 1996. MEIC is a voluntary effort by international laboratories to test the same 50 reference chemicals in their own in vitro toxicity systems. At present, 31 laboratories have submitted results for the first 30 reference chemicals from a total of 68 in vitro cytotoxicity tests. In the definitive evaluation of the MEIC programme, these in vitro results will be compared with human lethal blood concentrations and other relevant acute systemic toxicity data, and the results will be published as a series of articles. This paper, which is the first article in this series, describes and analyses the methodologies used in the 68 tests. The origins and purities of the test chemicals, the biological systems and the toxicity endpoints are also discussed. Since MEIC is not centrally directed, the selection of tests was entirely dependent on the preferences of the individual laboratories. Thus, the collection of tests is not representative of the full range of existing in vitro toxicity tests. In our study, basal cytotoxicity tests and ecotoxicological tests are prevalent, while tests for toxicity to primary cultures of differentiated cells, measured by organotypic toxicity endpoints, are clearly under-represented.

In vitro toxicology

10.1177/026119299602400102.1

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Citations (31)

Mechanism of N-acetylcysteine (NAC) and other thiols as both positive and negative modifiers of MNNG-induced mutagenicity in V79 Chinese hamster cells

Carcinogenesis (1987)

Lennart Romert Dag Jenssen

Journal Article Mechanism of N -acetylcysteine (NAC) and other thiols as both positive and negative modifiers of MNNG-induced mutagenicity in V79 Chinese hamster cells Get access Lennart Romert, Lennart Romert Department of Genetic and Cellular Toxicology, Wallenberg Laboratory, University of StockholmS-106 91 Stockholm, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Dag Jenssen Dag Jenssen Department of Genetic and Cellular Toxicology, Wallenberg Laboratory, University of StockholmS-106 91 Stockholm, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Carcinogenesis, Volume 8, Issue 10, October 1987, Pages 1531–1535, https://doi.org/10.1093/carcin/8.10.1531 Published: 01 October 1987 Article history Received: 22 April 1987 Accepted: 03 July 1987 Published: 01 October 1987

Methylnitronitrosoguanidine

Reactive intermediate

Chinese hamster

10.1093/carcin/8.10.1531

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Citations (23)

Effects of glutathione transferase activity on benzo[a]pyrene 7,8-dihydrodiol metabolism and mutagenesis studied in a mammalian cell co-cultivation assay

Carcinogenesis (1989)

Lennart Romert Lennart Dock Dag Jenssen Bengt Jernström

This study deals with the role of glutathione transferase (GST)-mediated conjugation of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE) in two mammalian cell lines, human mammary carcinoma cells (MCF-7) and rat hepatoma cells (H4IIE), in relation to their capacity to metabolize (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)-BP-7,8-diol] to products that induce mutations in co-cultivated V79 cells. Both MCF-7 and H4IIE cells metabolized (-)-BP-7,8-diol to BPDE, but mutations in co-cultivated V79 cells were only detected with MCF-7 cells. However, depletion of glutathione (GSH) in H4IIE cells increased the mutagenicity of (-)-BP-7,8-diol to a similar level to that found with MCF-7 cells. Measurements of GST activity using GSH and post-microsomal supernatants from H4IIE, V79 and MCF-7 cells indicated a substantial difference in conjugation capacity. Although preparations from all three cell-lines showed GST activity with 1-chloro-2,4-dinitrobenzene as the substrate, GST activity towards BPDE could only be detected in supernatants from H4IIE cells. This is consistent with the presence of GST 7-7 an isoenzyme highly efficient in catalysing BPDE-GSH conjugation. The difference in GSH-conjugation activity towards BPDE was confirmed using intact H4IIE and MCF-7 cells in culture. These results indicate that GSH-conjugation plays a pivotal role in mutagenesis induced by polycyclic aromatic hydrocarbons (PAH). Accordingly, a deficiency in GSH-conjugation capacity may be regarded as one important factor in defining a target cell population with an increased risk for tumour initiation following exposure to PAH.

10.1093/carcin/10.9.1701

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Citations (45)

Comparison of the toxicity of 30 chemicals as measured by 85 different in vitro toxicity tests

Toxicological Sciences (1995)

B. Ekwall Elizabeth M. Abdulla Fabio Barile C. Chesné Richard Clothier

Source

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Multivariate Validation of Cell Toxicity Data: The First Ten MEIC Chemicals

Alternatives to Laboratory Animals (1990)

Sven Hellberg Inger Bondesson Björn Ekwall María José Gómez‐Lechón Ramiro Jover

The MEIC project is designed to evaluate the relevance of cytotoxicity data to the prediction of human toxicity. The large number of cytotoxicity tests and endpoints available makes it necessary to apply multivariate data-analytical methods in the evaluation procedure. PLS analysis of the cytotoxicity data collected so far for the first ten MEIC compounds indicate that the data are relevant for human toxicity. However, it was also apparent that the 14 cytotoxicity tests only showed slight differences, indicating that there is a need for other cytotoxicity tests (or endpoints) containing complementary information.

10.1177/026119299001700322

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Citations (4)

MEIC evaluation of acute systemic toxicity .2. In vitro results from 68 toxicity assays used to test the first 30 reference chemicals and a comparative cytotoxicity analysis.

Alternatives to Laboratory Animals (1996)

Cecilia Clemedson Elisabeth McFarlane-Abdulla Maria A. Andersson Fa Barile M.C. Calleja

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Citations (3)

Cytotoxicity Evaluation of the First Ten MEIC Chemicals: Acute Lethal Toxicity in Man Predicted by Cytotoxicity in Five Cellular Assays and by Oral LD50 Tests in Rodents

Alternatives to Laboratory Animals (1989)

Björn Ekwall Inger Bondesson José V. Castell María José Gómez‐Lechón Sven Hellberg

The MEIC (multicentre evaluation of in vitro cytotoxicity) programme is a five-year programme to validate in vitro tests for general toxicity, and is organised by the Scandinavian Society for Cell Toxicology. Interested laboratories are invited, on an international basis, to test 50 published reference chemicals in their respective assays. Submitted results will then be evaluated yearly by the MEIC Committee for their relevance to various types of human toxicity, including an evaluation for the same chemicals of the prediction by animal tests of human toxicity. To establish the validation methods, a preliminary validation cycle is being performed in 1989/90 with submitted results for the first ten MEIC chemicals. The present paper is the very first step of this preliminary validation process. The prediction of human toxicity by five cytotoxicity assays (altogether 14 different cell systems/endpoints) has been evaluated, and also compared with the predictive value of rodent LD50 tests. Mouse LD50 prediction of human lethal dosage for these substances was good, while rat LD50 prediction was less satisfactory. The collective predictions by all 14 cell systems/endpoints of human toxicity in the form of a multivariate PLS (partial least squares) model of human acute lethal blood concentrations, as well as the corresponding prediction by a HeLa cell assay, were comparable to the efficiency of mouse LD50 prediction of human lethal dosage. When combined with simple toxicokinetic data (absorption of chemicals in the intestine and distribution volumes), the PLS model and the HeLa assay were able to predict human lethal dosage of the ten chemicals as accurately as the mouse LD50 value. The small number of chemicals studied to date means that general conclusions cannot be drawn from these results. Further validation of more chemicals with the in vitro methods is essential and promises to be worthwhile.

Median lethal dose

HeLa

In vitro toxicology

10.1177/026119298901700205

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Citations (73)