Abstract Title:

Unexpected common mechanistic pathways for embryotoxicity of warfarin and lovastatin.

Abstract Source:

Reprod Toxicol. 2010 Aug;30(1):121-30. Epub 2010 May 20. PMID: 20493250

Abstract Author(s):

Karlfried Groebe, Katrin Hayess, Martina Klemm-Manns, Gerhard Schwall, Woijciech Wozny, Margino Steemans, Annelieke K Peters, Chaturvedala Sastri, Petra Jaeckel, Werner Stegmann, Helmut Zengerling, Rainer Schöpf, Slobodan Poznanovic, Tina C Stummann, Andrea Seiler, Horst Spielmann, André Schrattenholz

Article Affiliation:

ProteoSys AG, Mainz, Germany.


Novel molecular content for fast in vitro strategies in the context of safety tests concerning developmental toxicity has a potential to substantially reduce animal experiments according to the "3R" concept (Reduce/Refine/Replace). Here we present and discuss data from a differential proteomic profiling of samples generated using embryonic stem cell derived in vitro models treated with a set of model substances. Among substance-dependent proteomic changes, potential surrogate markers were some isoforms of heat shock proteins and a component of the Ras pathway, present in several redundant isoforms due to posttranslational modifications. Both proteins are implicated in cell migration, cell survival, growth and embryonic development. Using the examples of warfarin and lovastatin, two substances with entirely different primary targets, the surrogate marker signature nevertheless indicates a common embryotoxic mode of action. We discuss these findings observed in in vitro toxicity tests, in a context of clinical validation and evidence-based toxicology.

Study Type : In Vitro Study

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