Unexpected common mechanistic pathways for embryotoxicity of warfarin and lovastatin.
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.
Groebe
Karlfried
K
ProteoSys AG, Mainz, Germany.
Hayess
Katrin
K
Klemm-Manns
Martina
M
Schwall
Gerhard
G
Wozny
Woijciech
W
Steemans
Margino
M
Peters
Annelieke K
AK
Sastri
Chaturvedala
C
Jaeckel
Petra
P
Stegmann
Werner
W
Zengerling
Helmut
H
Schöpf
Rainer
R
Poznanovic
Slobodan
S
Stummann
Tina C
TC
Seiler
Andrea
A
Spielmann
Horst
H
Schrattenholz
André
A
D016475:3T3 Cells; D000826:Animal Testing Alternatives; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D023381:Endpoint Determination; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D020128:Inhibitory Concentration 50; D008148:Lovastatin / Q000633:toxicity*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D015203:Reproducibility of Results; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards; D014859:Warfarin / Q000633:toxicity*; D018631:ras Proteins / Q000096:biosynthesis
D006360:Heat-Shock Proteins; D013723:Teratogens; D014859:Warfarin; D008148:Lovastatin; D018631:ras Proteins