Genoprotective pathways. II. Attenuation of oxidative DNA damage by isopentenyl diphosphate

Oxidative stress is believed to play a role in the pathogenesis of many diseases. Here we report that isopentenyl diphosphate (IPP), the 5-carbon building unit of all isoprenoids, is a potent antioxidant that is capable of inhibiting oxidative DNA damage at picomolar concentrations (IC50 = 1.7 x 10(-11) M). The diphosphate moiety is essential, since isopentenyl monophosphate (IMP) is unable to trigger antioxidative signaling. The 20-carbon isoprenyl, geranylgeranyl diphosphate (GGPP), but not the 15-carbon farnesyl diphosphate, displays similar genoprotective effects. The pathway activated by IPP is distinct from that of 2-chloroadenosine (2CA). 2CA-mediated genoprotective signaling is transduced through an A2a or A2b adenosine receptor (AR) and can be blocked by the cyclic AMP (cAMP)-dependent protein kinase (PKA) inhibitor, H-89. In contrast, IPP signaling is independent of A2aAR, A2bAR, cAMP or PKA. Unlike the 2CA-mediated pathway, the effect of IPP is dependent on the mevalonate pathway, a geranylgeranylated protein and on intact proteasome activity. Thus, IPP is a potent activator of a novel genoprotective pathway. These findings shed new light on the role of isoprenoids in oxidative stress biology and may help to develop novel preventive strategies against oxidative damage.