Project

Discipline

epoxide hydrolase; carbonyl reduction; endoplasmic reticulum; metabolism; detoxification; glucocorticoid; cytochrome P450

Lead
Prof. Arand's project revealed an important interaction between a cytochrome P450 monooxygenase and the microsomal epoxide hydrolase, explaning the efficient detoxification of epoxides. Prof. Odermatt's project studied the role of an oxidoreductase in the metabolism of the fungicide triadimefon and the anti-depressant drug bupropion. This enzyme also activates glucocorticoids. Thus, these findings are important regarding potential drug-drug interactions.
Lay summary
The research module "The role of the endoplasmic reticulum in the metabolism of xenobiotics" is part of the ProDoc Education Module "Predictive Toxicology". The uptake, distribution, metabolism and excretion of nutrients and drugs are essentially regulated in the intestine, liver and kidneys by a coordinated action of receptors, transport proteins and metabolizing enzymes. This allows living organisms to cope with toxic chemicals taken up by food (adaptation to food availability and quality), metabolites of drugs, and toxic endogenous chemicals (hormone metabolites, oxidized fat). To improve the toxicity prediction, the function of the enzymes, receptors and transporters involved in detoxification reactions need to be understood in the context of the situation of these proteins inside a given cell. Thus, the exact intracellular localization of these proteins and the impact of the conditions in a specific compartment inside a cell need to be elucidated, and appropriate assay systems have to be developed for safety assessment of chemicals. This research module addresses the role of the endoplasmic reticulum (ER) in the metabolism of exogenous and endogenous chemicals, and the role of altered ER function for the metabolism and toxicity of chemicals. The ER plays an important role in the detoxification of xenobiotics and endogenous metabolites. Therefore, elucidation of the consequences of impaired ER function for the metabolism and toxicity of xenobiotics is important regarding the development of safer drugs. Specifically, this project focuses on the elucidation of 1) the impact of the membrane topology of microsomal epoxide hydroxylase and its allelic variants on substrate turnover/detoxification efficacy, and 2) on the identification of xenobiotics metabolizing short-chain dehydrogenase/reductases in the ER and the investigation of the impact of impaired ER function on xenobiotics metabolism. A range of different in vitro assays, cell- and animal models are applied in order to study the functions of enzymes in the ER and to assess the impact of altered ER function on the metabolism and toxicity of xenobiotics. The proposed research is relevant for uncovering basic mechanisms of the metabolism of endogenous and exogenous compounds in health and disease states. The knowledge gained from the proposed research is relevant for safety considerations for drugs and industrial chemicals. The proposed projects provide a unique opportunity for the establishment of collaborations and provide a multidisciplinary training opportunity across multiple areas of the Predictive Toxicology program.

Direct link to Lay Summary

Last update: 21.05.2013

Active participation

Number	Title	Start	Funding scheme

The uptake, distribution, metabolism and excretion of nutrients and drugs are essentially regulated in the intestine, liver and kidneys by a coordinated action of receptors, transport proteins and metabolizing enzymes. This allows living organisms to cope with toxic chemicals taken up by food (adaptation to food availability and quality), metabolites of drugs and toxic endogenous compounds (e.g. metabolites of hormones, oxidized lipids and fatty acids). There is an extensive knowledge on enzymes involved in xenobiotic metabolism, mostly focusing on cytoplasmic enzymes and cytochrome P450 (CYP), a microsomal enzyme with its catalytic domain facing the cytoplasm. In contrast, other xenobiotic-metabolizing enzymes located in the endoplasmic reticulum (ER) are often less well investigated. Also, the elucidation of the consequences of distur-bances of ER function, such as ER-stress and altered ER redox state, for the metabolism and toxicity of chemicals requires further research. This research module is proposed by two groups of human toxicologists who focus on the investigation of the role of the ER in the metabolism of exogenous and endogenous chemicals as well as on the role of altered function of the ER for the metabolism and toxicity of chemicals. In particular, our proposal for a Prodoc research module comprises the following three research topics:1.Impact of the membrane topology of microsomal epoxide hydroxylase (mEH) on substrate turnover/detoxication efficacy (Michael Arand),2.Identification of xenobiotic metabolizing short-chain dehydrogenase/reductase (SDR) enzymes in the ER and investigation of the impact on xenobiotic metabolism (Alex Odermatt).Adverse drug effects often manifest in only very few subjects and the underlying mechanisms are mostly unknown. Genetic differences, environmental factors and health state can significantly influence the efficacy of drugs as well as their adverse effects. The ER plays an important role in the detoxification of xenobiotics and endogenous metabolites; therefore, elucidation of the consequences of impaired ER function for the metabolism and toxicity of xenobiotics is of great interest regarding the development of safer drugs. To achieve our goal, we will use a range of different in vitro assays, cellular model systems and animal models to study the functions of transporters and enzymes in the ER and to assess the impact of altered function of the ER on the metabolism and toxicity of xenobiotics. The proposed research is relevant for uncovering basic mechanisms of the metabolism of endogenous and exogenous compounds in health and disease states. Furthermore, the knowledge gained from the proposed research is relevant for safety considerations for drugs and industrial chemicals. The proposed projects provide a unique opportunity for the establishment of collaborations and provide a multidisciplinary training opportunity across multiple areas of the Predictive Toxicology program. Top-ranking students selected from candidates who are admitted to the “Predictive Toxicology” PhD program will be able to choose a project among the three research topics.