Thalidomide - Teratogenic Mechanism

Teratogenic Mechanism

The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms. A theoretical synthesis in 2000 suggested the following mechanism: thalidomide intercalates (inserts itself) into DNA in guanine-cytosine-rich regions. Owing to its glutarimide part, (S) thalidomide fits neatly into the major groove of DNA at purine sites. Such intercalation impacts upon the promoter regions of the genes controlling the development of limbs, ears, and eyes, such as IGF-I and FGF-2. These normally activate the production of the cell surface attachment integrin αvβ3, with the resulting αvβ3 integrin dimer stimulating angiogenesis in developing limb buds. This then promotes the outgrowth of the bud (IGF-I and FGF-2 are also both known to stimulate angiogenesis). Therefore, by inhibiting the chain of events, thalidomide causes the truncation of limb development. In 2009, this theory received strong support, with research showing "conclusively that loss of newly formed blood vessels is the primary cause of thalidomide teratogenesis, and developing limbs are particularly susceptible because of their relatively immature, highly angiogenic vessel network". The inhibition of the growth of blood vessels, once understood, is beneficial in treating some disorders in patients who are definitively known not to be pregnant.

Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. The enantiomers can interconvert (racemize) in vivo – that is, if a human male is given pure (R)-thalidomide or (S)-thalidomide, both isomers will later be found in his serum – therefore, on balance of probabilities, administering only one enantiomer in a human female will not prevent the teratogenic effect. The mechanism (eg. organ) for this phenomenon is apparently ill-understood.