Keratinocyte cell-mediated mutagenesis assay: Correlation with in vivo tumor studies

John J. Reiners; Larry P. Yotti; Catherine K. Mckeown; Stephen Nesnow; Thomas J. Slaga

doi:10.1093/carcin/4.3.321

Keratinocyte cell-mediated mutagenesis assay: Correlation with in vivo tumor studies

John J. Reiners, Larry P. Yotti, Catherine K. Mckeown, Stephen Nesnow, Thomas J. Slaga

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activation of promutagens and Chinese hamster lung V-79 fibroblasts for detection of resulting mutagens. Mutations at, or affecting, the hypoxanthine-guanine phosphoribosyltransferase locus were scored by resisistance to 6-thioguanine. The relative mutagenicities of several polycyclic aromatic hydrocarbons (PAHs) in the cell-mediated assay correlated with the in vivo skin tumongenicity of the PAHs determined in a two-stage carcinogenesis protocol. Metabolic activation of the promutagenic PAHs to ultimate mutagens was dependent upon the presence of the cultured keratinocyte feeder layer. 7,8-Benzoflavone, a potent inhibitor of 7, 12-dimethylbenz- [a]anthracene (DMBA)-dependent initiation in mouse skin, inhibited DMBA-dependent mutagenesis in the cell-mediated assay in a concentration responsive manner. The non-PAH promutagens, dimethylnitrosamine (DMN) and sterigmatocystin (STC) were both activated by cultured keratinocytes to cytotoxic derivatives. DMN was neither mutagenic in the cell-mediated assay nor tumorigenic in mouse skin when tested in a two-stage carcinogenesis protocol. STC was weakly mutagenic and tumorigenic in mouse skin.

Original language	English (US)
Pages (from-to)	321-326
Number of pages	6
Journal	Carcinogenesis
Volume	4
Issue number	3
DOIs	https://doi.org/10.1093/carcin/4.3.321
State	Published - 1983
Externally published	Yes

ASJC Scopus subject areas

Cancer Research

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10.1093/carcin/4.3.321

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@article{143806920db64e92a96ea7eb08b1b38a,

title = "Keratinocyte cell-mediated mutagenesis assay: Correlation with in vivo tumor studies",

abstract = "A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activation of promutagens and Chinese hamster lung V-79 fibroblasts for detection of resulting mutagens. Mutations at, or affecting, the hypoxanthine-guanine phosphoribosyltransferase locus were scored by resisistance to 6-thioguanine. The relative mutagenicities of several polycyclic aromatic hydrocarbons (PAHs) in the cell-mediated assay correlated with the in vivo skin tumongenicity of the PAHs determined in a two-stage carcinogenesis protocol. Metabolic activation of the promutagenic PAHs to ultimate mutagens was dependent upon the presence of the cultured keratinocyte feeder layer. 7,8-Benzoflavone, a potent inhibitor of 7, 12-dimethylbenz- [a]anthracene (DMBA)-dependent initiation in mouse skin, inhibited DMBA-dependent mutagenesis in the cell-mediated assay in a concentration responsive manner. The non-PAH promutagens, dimethylnitrosamine (DMN) and sterigmatocystin (STC) were both activated by cultured keratinocytes to cytotoxic derivatives. DMN was neither mutagenic in the cell-mediated assay nor tumorigenic in mouse skin when tested in a two-stage carcinogenesis protocol. STC was weakly mutagenic and tumorigenic in mouse skin.",

author = "Reiners, {John J.} and Yotti, {Larry P.} and Mckeown, {Catherine K.} and Stephen Nesnow and Slaga, {Thomas J.}",

note = "Funding Information: Research was sponsored by NCI Grant CA-20076 and by EPA Contract Number 79-D-X0526 under Interagency Agreement DOE Number 40-728-78 and the Office of Health and Environmental Research, U.S. Department of Energy, under Contract W-7405-eng-26 with the Union Carbide Corporation. L.Y. is a Postdoctoral Investigator supported by Subcontract No. 3322 from the Biology Division of Oak Ridge National Laboratory to the University of Tennessee. Although the research described in this article has been funded wholly or in part by the United States Environmental Protection Agency (EPA) through Interagency Agreement 40-728-78 to the U.S. Department of Energy it has not been subjected to EPA review and therefore does not necessarily reflect the views of EPA and no official endorsement should be inferred.",

year = "1983",

doi = "10.1093/carcin/4.3.321",

language = "English (US)",

volume = "4",

pages = "321--326",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - Keratinocyte cell-mediated mutagenesis assay

T2 - Correlation with in vivo tumor studies

AU - Reiners, John J.

AU - Yotti, Larry P.

AU - Mckeown, Catherine K.

AU - Nesnow, Stephen

AU - Slaga, Thomas J.

N1 - Funding Information: Research was sponsored by NCI Grant CA-20076 and by EPA Contract Number 79-D-X0526 under Interagency Agreement DOE Number 40-728-78 and the Office of Health and Environmental Research, U.S. Department of Energy, under Contract W-7405-eng-26 with the Union Carbide Corporation. L.Y. is a Postdoctoral Investigator supported by Subcontract No. 3322 from the Biology Division of Oak Ridge National Laboratory to the University of Tennessee. Although the research described in this article has been funded wholly or in part by the United States Environmental Protection Agency (EPA) through Interagency Agreement 40-728-78 to the U.S. Department of Energy it has not been subjected to EPA review and therefore does not necessarily reflect the views of EPA and no official endorsement should be inferred.

PY - 1983

Y1 - 1983

N2 - A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activation of promutagens and Chinese hamster lung V-79 fibroblasts for detection of resulting mutagens. Mutations at, or affecting, the hypoxanthine-guanine phosphoribosyltransferase locus were scored by resisistance to 6-thioguanine. The relative mutagenicities of several polycyclic aromatic hydrocarbons (PAHs) in the cell-mediated assay correlated with the in vivo skin tumongenicity of the PAHs determined in a two-stage carcinogenesis protocol. Metabolic activation of the promutagenic PAHs to ultimate mutagens was dependent upon the presence of the cultured keratinocyte feeder layer. 7,8-Benzoflavone, a potent inhibitor of 7, 12-dimethylbenz- [a]anthracene (DMBA)-dependent initiation in mouse skin, inhibited DMBA-dependent mutagenesis in the cell-mediated assay in a concentration responsive manner. The non-PAH promutagens, dimethylnitrosamine (DMN) and sterigmatocystin (STC) were both activated by cultured keratinocytes to cytotoxic derivatives. DMN was neither mutagenic in the cell-mediated assay nor tumorigenic in mouse skin when tested in a two-stage carcinogenesis protocol. STC was weakly mutagenic and tumorigenic in mouse skin.

AB - A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activation of promutagens and Chinese hamster lung V-79 fibroblasts for detection of resulting mutagens. Mutations at, or affecting, the hypoxanthine-guanine phosphoribosyltransferase locus were scored by resisistance to 6-thioguanine. The relative mutagenicities of several polycyclic aromatic hydrocarbons (PAHs) in the cell-mediated assay correlated with the in vivo skin tumongenicity of the PAHs determined in a two-stage carcinogenesis protocol. Metabolic activation of the promutagenic PAHs to ultimate mutagens was dependent upon the presence of the cultured keratinocyte feeder layer. 7,8-Benzoflavone, a potent inhibitor of 7, 12-dimethylbenz- [a]anthracene (DMBA)-dependent initiation in mouse skin, inhibited DMBA-dependent mutagenesis in the cell-mediated assay in a concentration responsive manner. The non-PAH promutagens, dimethylnitrosamine (DMN) and sterigmatocystin (STC) were both activated by cultured keratinocytes to cytotoxic derivatives. DMN was neither mutagenic in the cell-mediated assay nor tumorigenic in mouse skin when tested in a two-stage carcinogenesis protocol. STC was weakly mutagenic and tumorigenic in mouse skin.

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U2 - 10.1093/carcin/4.3.321

DO - 10.1093/carcin/4.3.321

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EP - 326

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 3

ER -

Keratinocyte cell-mediated mutagenesis assay: Correlation with in vivo tumor studies

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