Structure-specificity of the genotoxicity of some naturally occurring alkenylbenzenes determined by the unscheduled DNA synthesis assay in rat hepatocytes

Prediction of rodent carcinogenicity using the DEREK system for 30 chemicals currently being tested by the National Toxicology Program. The DEREK Collaborative Group.

“…Methyleugenol gave a negative response in the Ames test and a mouse micronucleus assay, although a positive response has been reported in an in vitro unscheduled DNA synthesis (UDS) assay (35). It has been suggested that a lack of activity of alkenylbenzenes in the Ames test is most likely to be due to the failure of metabolic activation (35). Methyleugenol has also been reported to induce hepatic tumors in male mice treated prior to weaning (36).…”

2,4,5-trimethoxycinnamic acid: the major metabolite of α-asarone, retains most of the pharmacological properties of α-asarone

“…It has been demonstrated that a-asarone possess hypocholesterolemic [2,3,4] and hypolipidemic properties [3] due to the inhibition of HMG-CoA reductase [4], however a-asarone cannot be used in clinical trials due to its genotoxic and hepatocarcinogenic properties in rodents [5,6]. On the contrary, TMC, the major metabolite of a-asarone, does not have the above mentioned toxicological effects [6].…”

“…These findings could explain the hypocholesterolemic and the cholelitholytic properties of a-asarone. It has also been demonstrated that a-asarone possess genotoxic [5,6] and hepatocarcinogenic properties in rodents [7]. Therefore, a-asarone cannot be used in clinical trials.…”

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

“…Safrole was shown to increase UDS in primary rat hepatocytes and HeLa cells at concentrations of 0.000 162-1620 μg/ml (Michalopoulos et al, 1978;Althaus et al, 1982;Williams, 1984;Barrett, 1985;Glauert et al, 1985;Martin & Campbell, 1985;Williams et al, 1985;Howes et al, 1990b). It should be noted that at concentrations greater than 162 μg/ml, safrole is highly cytotoxic (Burkey et al, 2000).…”