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- W1581948944 abstract "The herbal constituents safrole, estragole, and methyleugenol, belonging to the chemical class of the alkenylbenzenes, are genotoxic and carcinogenic compounds. The genotoxicity of these alkenylbenzenes proceeds via electrophilic metabolites generated by cytochrome P450 enzymes (P450) and sulfotransferases (SULT). Carcinogenicity of these compounds was demonstrated in animal experiments using relatively high doses of single compounds. Human exposure to these compounds is much lower than the doses used in the animal experiments and humans are exposed to alkenylbenzenes in a complex food matrix. The first aim of this thesis was to identify the human P450 enzymes that are responsible for the bioactivation of the alkenylbenzenes into their proximate carcinogenic 1 ¢ - hydroxymetabolites . Several in vitro studies using recombinant P450 enzymes and human liver microsomes were undertaken to identify the main enzymes involved in the 1 ¢ -hydroxylation of the alkenylbenzenes and to determine their kinetics. These studies showed that at low substrate concentrations, P450 1A2 is the major enzyme in the bioactivation of methyleugenol , P450 1A2 and P450 2A6 are the main enzymes in the bioactivation of estragole , and P450 2A6 is the main enzyme in the bioactivation of safrole . The second objective of this thesis was to study the influence of other herbal constituents on the bioactivation and the genotoxicity of herb-based alkenylbenzenes . An on-line high-performance liquid chromatography detection system was developed for the detection of P450 1A2 inhibitors in herbal extracts. The presence of P450 1A2 inhibitors in basil, a herb that contains methyleugenol and estragole , was demonstrated using this on-line system. In addition to these P450 1A2 inhibitors, also the alkenylbenzenes themselves may act as inhibitors competing for the active site of P450 1A2 ( estragole and methyleugenol ) or P450 2A6 ( estragole and safrole ). Furthermore it was demonstrated that basil extract is able to strongly inhibit sulfation and subsequent DNA adduct formation of 1 ¢ - hydroxyestragole in incubations with rat and human S9 homogenates and in the human hepatoma HepG2 cell line. These in vitro results suggest that P450- and SULT-catalyzed bioactivation of methyleugenol and/or estragole and subsequent adverse effects may be lower in a matrix of other herbal components than what would be expected on the basis of experiments using single compounds. In vivo experiments have to point out whether the protective effects that are found in these in vitro studies can be extrapolated to the in vivo situation. It may turn out that rodent carcinogenicity data on estragole and methyleugenol considerably overestimate the risks posed when humans are exposed to these compounds in a herbal matrix." @default.
- W1581948944 created "2016-06-24" @default.
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- W1581948944 date "2007-01-01" @default.
- W1581948944 modified "2023-09-28" @default.
- W1581948944 title "Bioactivation and genotoxicity of the herbal constituents safrole, estragole and methyleugenol" @default.
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