Hamster hepatocyte-mediated activation of procarcinogens to mutagens in the L5178Y/TK mutation assay

Amacher, David E.; Paillet, Simone C.

doi:10.1016/0027-5107(82)90112-9

Cited by 10 publications

(3 citation statements)

References 17 publications

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“…However, the disruption of cell membranes, alteration of intracellular organization, and loss of soluble enzymes and cofactors in S9 preparations may make intact cells a more relevant system for the evaluation of metabolic activation. The ability to use isolated hepatocytes as an alternative to liver homogenates as an exogenous activation system has been successfully demonstrated in mammalian cell mutagenesis assays [Langenbach et al, 1978;Michalopoulos et al, 1981;Amacher and Paillet, 1982;Bermudez et al, 1982;Casciano and Shaddock, 19821, sister chromatid exchange assays [Kligerman et al, 1980;Karlberg and Lindahl-Kiessling, 1981;Madle et al, 19861 and the Salmonella typhimurium histidine reversion assay [Gayda and Pariza, 1981;Bos et al, 1983;Kerklaan et al, 19831. Our data in this study have demonstrated that cryopreserved hepatocytes can be successfully used in place of freshly isolated hepatocytes as an activating system.…”

Section: Discussionmentioning

confidence: 99%

Promutagen activation by freshly isolated and cryopreserved rat hepatocytes

Loretz¹,

Wilson²,

Li³

1988

Environ. mutagen

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The metabolic activation of promutagens by freshly isolated and cryopreserved rat hepatocytes was compared using the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyltransferase assay (CHOIHGPRT). Cryopreserved rat hepatocytes were equivalent to freshly isolated hepatocytes in their ability to metabolize dimethylbenz(a)anthracene (DMBA) and dimethylnitrosamine (DMN) to active mutagens. Similar dose-response curves were observed using either freshly isolated or cryopreserved hepatocytes as activating systems after treatment with DMBA (0.1-1 pglml) and DMN (0.075-0.6 mg/ml). Our results suggest that cryopreserved hepatocytes are similar to freshly isolated hepatocytes as an experimental system for studies on promutagen activation.

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Section: Discussionmentioning

confidence: 99%

Promutagen activation by freshly isolated and cryopreserved rat hepatocytes

Loretz¹,

Wilson²,

Li³

1988

Environ. mutagen

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“…Positive results were reported in Salmonella Typhimurium strain TA100 and in Escherichia coli uvrA in the presence of metabolic activation by hamster and rat liver S9 (with enhanced NDMA mutagenicity by hamster S9) (Araki et al, 1984 ). In mammalian cells, NDMA induced gene mutations in mouse lymphoma cells in the presence of an exogenous metabolic system from Syrian hamster cells (Amacher and Paillet, 1982 ). In the absence of an exogenous metabolic activation system, no induction of micronuclei was observed in cultured isolated lymphocytes (Katic et al, 2010 ), while a significant increase of micronuclei frequency was reported in the human hepatoma‐derived HepG2 cells (Majer et al, 2004 ).…”

Section: Assessmentmentioning

confidence: 99%

“…It induced reverse mutations in bacteria in the presence of an exogenous metabolic system (Yahagi et al, 1977 ; Araki et al, 1984 ) and in host‐mediated assays in mice. In mammalian cells, NDEA induced chromosomal aberrations and SCEs in the presence of an exogenous metabolic system in Chinese hamster cells (Ishidate Jr and Odashima, 1977 ) and gene mutations in mouse lymphoma cells (Amacher and Paillet, 1982 ).…”

Section: Assessmentmentioning

confidence: 99%

Risk assessment of N‐nitrosamines in food

Schrenk¹,

Bignami²,

Bodin³

et al. 2023

EFS2

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EFSA was asked for a scientific opinion on the risks to public health related to the presence of Nnitrosamines (N-NAs) in food. The risk assessment was confined to those 10 carcinogenic N-NAs occurring in food (TCNAs), i.e. NDMA, NMEA, NDEA, NDPA, NDBA, NMA, NSAR, NMOR, NPIP and NPYR. N-NAs are genotoxic and induce liver tumours in rodents. The in vivo data available to derive potency factors are limited, and therefore, equal potency of TCNAs was assumed. The lower confidence limit of the benchmark dose at 10% (BMDL 10 ) was 10 μg/kg body weight (bw) per day, derived from the incidence of rat liver tumours (benign and malignant) induced by NDEA and used in a margin of exposure (MOE) approach. Analytical results on the occurrence of N-NAs were extracted from the EFSA occurrence database (n = 2,817) and the literature (n = 4,003). Occurrence data were available for five food categories across TCNAs. Dietary exposure was assessed for two scenarios, excluding (scenario 1) and including (scenario 2) cooked unprocessed meat and fish. TCNAs exposure ranged from 0 to 208.9 ng/kg bw per day across surveys, age groups and scenarios. 'Meat and meat products' is the main food category contributing to TCNA exposure. MOEs ranged from 3,337 to 48 at the P95 exposure excluding some infant surveys with P95 exposure equal to zero. Two major uncertainties were (i) the high number of left censored data and (ii) the lack of data on important food categories. The CONTAM Panel concluded that the MOE for TCNAs at the P95 exposure is highly likely (98-100% certain) to be less than 10,000 for all age groups, which raises a health concern.

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Comparison of mutagenicities in a salmonella reversion assay mediated by uninduced hepatocytes and hepatocytes from rats pretreated for 1 or 5 days with aroclor 1254

et al. 1985

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Hepatocytes prepared from rats pretreated for 5 days with 500 mg/kg Aroclor 1254 were found to be unsuitable for use in a modified Salmonella mutagenicity assay. These hepatocytes exhibited low viability, did not readily attach to plastic culture dishes, and produced mutagenicity responses with benzo[a]pyrene (B[a]P) and 2-aminofluorene (2AF) that were greatly enhanced by the addition of an NADPH-regenerating system (NADPH-RS). Shortening the Aroclor pretreatment time to 1 day resulted in hepatocytes that exhibited high viability and readily attached to plastic culture dishes. These hepatocytes produced higher numbers of revertants when used to assay the mutagenicities of B[a]P and 2AF than were produced using hepatocytes from animals that were pretreated for 5 days. These reversion frequencies were also higher than those produced using uninduced hepatocytes and were much less affected by the addition of NADPH-RS than were the reversions mediated by the 5-day preinduced hepatocytes. Liver homogenate postmitochondrial fractions (S9s), which were prepared from rats pretreated with Aroclor for 1 or 5 days, were nearly equal in their ability to mediate the mutagenicity of B[a]P and 2AF in the Salmonella/microsome reversion assay. Qualitative differences between the S9- and hepatocyte-mediated mutagenicity of 2AF were found, however. These results indicate that employing hepatocytes from rats pretreated with Aroclor for 1 day, rather than 5 days, results in an enzymatically induced, more-intact cell population that is capable of detecting the mutagenicity of B[a]P and 2AF in a modified Salmonella reversion assay.

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Hamster hepatocyte-mediated activation of procarcinogens to mutagens in the L5178Y/TK mutation assay

Cited by 10 publications

References 17 publications

Promutagen activation by freshly isolated and cryopreserved rat hepatocytes

Promutagen activation by freshly isolated and cryopreserved rat hepatocytes

Risk assessment of N‐nitrosamines in food

Comparison of mutagenicities in a salmonella reversion assay mediated by uninduced hepatocytes and hepatocytes from rats pretreated for 1 or 5 days with aroclor 1254

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