Structure-specificity of the genotoxicity of some naturally occurring alkenylbenzenes determined by the unscheduled DNA synthesis assay in rat hepatocytes.
A number of alkenylbenzenes related to safrole and estragole are known to be hepatocarcinogenic in rats and/or mice, apparently by a genotoxic mechanism. However, they are not bacterial mutagens in the Ames test. We have studied the ability of a series of carcinogenic and non-carcinogenic congeners to induce unscheduled DNA synthesis (UDS) in freshly isolated rat hepatocytes in primary culture. The cytotoxicity of these compounds was assessed by lactate dehydrogenase leakage. There was an excellent correlation between UDS induction and known rodent hepatocarcinogenicity, with safrole, estragole and methyleugenol all inducing UDS. Anethole, isosafrole, eugenol and allylbenzene, for which evidence of carcinogenicity is equivocal or negative, did not induce UDS. All compounds were markedly cytotoxic at concentrations between 10(-3) and 10(-2) M, irrespective of their structural features. The data are discussed with reference to the known structure dependence of the disposition of the alkenylbenzenes, notably their metabolic activation, with which there are excellent correlations. The demonstration of the genotoxicity of rodent hepatocarcinogenic alkenylbenzenes in cells cultured from the in vivo target organ will allow the direct investigation of factors influencing these processes and facilitate the safety evaluation of these important natural flavours.
Howes
A J
AJ
Department of Pharmacology and Toxicology, St Mary's Hospital Medical School, London, UK.
Chan
V S
VS
Caldwell
J
J
D000818:Animals; D001555:Benzene Derivatives / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair / Q000187:drug effects; D005421:Flavoring Agents / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D005421:Flavoring Agents; D004247:DNA; D007770:L-Lactate Dehydrogenase