Development and application of human cell lines engineered to metabolically activate structurally diverse environmental mutagens

C. I. Crespi; Robert Langenbach; Frank J. Gonzalez; Harry V. Gelboin; B. W. Penman

doi:10.1117/12.140238

9 March 1993 Development and application of human cell lines engineered to metabolically activate structurally diverse environmental mutagens

C. I. Crespi, Robert Langenbach, Frank J. Gonzalez, Harry V. Gelboin, B. W. Penman

Author Affiliations +

Proceedings Volume 1716, International Conference on Monitoring of Toxic Chemicals and Biomarkers; (1993) https://doi.org/10.1117/12.140238
Event: Environmental Sensing '92, 1992, Berlin, Germany

Abstract

Cytochromes P450 are responsible for the mutagenic/carcinogenic activation of many environmental promutagens/procarcinogens. These enzymes are present at highest concentrations in liver in vivo but are markedly absent in tester organisms for most in vitro mutagenicity test systems. Two approaches have been used to supply needed metabolic activation, incorporation of an extracellular activating system, usually derived from a rodent liver and introduction of activating enzymes into the target cell. The latter approach appears to result in a more sensitive testing system because of the close proximity of the activating enzymes and the target DNA. Human cell lines have been developed which stably express human cytochromes P450 and other cDNAs which have been introduced individually or in combination. The resulting cell lines are exquisitely sensitive to exposure to promutagens and procarcinogens. Mutagenicity is measured at the hypoxanthine phosphoribosyl transferase (hprt) and thymidine kinase (tk) gene loci. The most versatile cell line, designated MCL-5, stably express five cDNAs encoding all of the human hepatic P450s known to be principally responsible for known human procarcinogen activation. The induction of mutation is observed in MCL-5 cells upon exposure to ng/ml levels of model compounds such as nitrosamines, aflatoxin B₁ and benzo(a)pyrene. A lower volume mutagenicity assay has been developed for use with samples available in limited amounts. Human lymphoblast mutation assays have been used to screen for mutagenic activity sediment samples from a polluted watershed. Two sediment samples were found to have mutagenic activity to human lymphoblasts.

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C. I. Crespi, Robert Langenbach, Frank J. Gonzalez, Harry V. Gelboin, and B. W. Penman "Development and application of human cell lines engineered to metabolically activate structurally diverse environmental mutagens", Proc. SPIE 1716, International Conference on Monitoring of Toxic Chemicals and Biomarkers, (9 March 1993); https://doi.org/10.1117/12.140238

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Liver

Mode conditioning cables

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Chemical analysis

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