Metabolism and genotoxicity of phenylpropenes
DNA is continiously damaged, e.g. by chemicals that bind covalently to DNA. If the repair of such DNA adducts doesn’t work efficiently, the damaged DNA may lead to mutations and eventually to the formation of cancer. Many mutagenic compounds do not react readily with DNA but are transformed to reactive intermediates during metabolism which then can interact with or bind to DNA (so called bioactivation).
Such compounds are in the focus of our research. To identify the molecular reactions, mechanisms of bioactivation and the following biological responses, i.e. DNA repair, it is necessary to identify metabolic pathways of a compound in the organism, to synthesize the identified metabolites and to characterize their (geno)toxic properties.
We are especially interested in phenylpropenes (PP) like methyleugenol, safrole or asarone isomers. These compounds which are naturally occurring for instance in basil, nutmeg or calamus and thus are part of our daily nutrition, were early proven to be (hepato)carcinogenic to rodents.
Bioactivation of allylic phenylpropenes (PP)
The bioactivation of allylic PP (i.e. with a terminal 2-propenylic double-bond) takes place mainly in the liver and requires to subsequent metabolic transformations. These are a cytochrome P450 cytalyzed hydroxylation in 1′-position of the side-chain and the following sulfonation of the formed alcohol. The resulting 1′sulfoxy-compound is the ultimate carcinogen because it is unstable, cleaves inorganic sulfate odd leading to a highly reactive carbocation. The latter can covalently bind to DNA to form bulky adducts, which are mutagenic and tumorigenic.
Bioactivation of 2-propenylic phenylpropenes
It was early shown that PP with 1-propenylic side-chain such as alpha- and beta-asarone are not bioactivated via sulfonation. We investigated the hepatic metabolism of asarone-isomers using liver microsomes and showed that the main metabolic pathway of those compounds is the epoxidation of the trans- or cis-configured side-chain.
We were able to synthesize these asarone-epoxides (which were positively tested in the Ames fluctuation assay) and the corresponding DNA adducts to use them as standards for mass spectrometry analysis (LC-MS³). In primary rat hepatocytes treated with asarone isomers, we quantified these asarone-epoxide-derived DNA adducts in a dose- and time-dependent manner. This strengthened our hypothesis that the side-chain epoxides are the ultimate carcinogens of asarone isomers.
The relevance of results from high dose rodent studies on human health is a central question in toxicology. The overall aim of our research is to contribute to the risk assessment of the presented compopunds. This is important for the reason i) these compounds are part of our daily nutrition and ii) that for compounds that are both, genotoxic and carcinogenic, no threshold can be assumed below a potential harm to human health can be excluded.
Toxicologically Assessment of E-cigarette liquids
E-cigarettes are increasingly popular worldwide. However, the question how harmful they are is not fully answered yet. The sales volume in Germany increased from 5 million Euro in 2010 to now estimated 600 million Euro in 2018. About four million people in Germany are frequent “vaper”. The fact that the emission of electronic cigarettes contains no or much lower concentrations of certain known tobacco-specific carcinogens (as far as we know by now) makes e-cigarettes for many (ex)smokers to a perfect and “healthier” substitute. E-cigarettes heat up a liquid which consists of propylene glycol, glycerine and facultatively nicotine, flavors, water or ethanol and the forming steam is inhaled by the user. Although it is accepted by many scientists and physicians that e-cigarettes pose a lower health risk, it is by no means proven, that they pose no risk at all.
We investigate analytically which potentially toxic compounds may be formed during the heating process of e-cigarette liquids and phenomenologically which toxic effects these compounds may have.