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.
PY - 1983/12/1
Y1 - 1983/12/1
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
M3 - Article
C2 - 6831637
AN - SCOPUS:0020611920
VL - 4
SP - 321
EP - 326
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 3
ER -