EFFECT OF GLUTATHIONE DEPLETION ON NRF2/ARE ACTIVATION BY DELTAMETHRIN IN

Transcription factor NF-E2-related factor 2 (Nrf2) is important for cell protection against chemical-induced oxidative stress. Previously, we have reported that in PC12 cells, Nrf2 can be triggered by deltamethrin (DM), a commonly used pyrethroid insecticide. Molecular mechanisms behind Nrf2 activation by DM are still unclear. Here we studied the effects of cell glutathione (GSH) depletion on Nrf2 activation by DM. We found that DM enhanced Nrf2 expression at the mRNA and protein levels and increased nuclear Nrf2 levels. Activation of Nrf2 was associated with activation of its downstream targets, such as heme oxygenase-1 (HO-1) and glutamate cysteine ligase catalytic subunit (GCLC). In contrast, DL-buthionine-[S,R]-sulfoximine (BSO), a known GSH-depleting agent, did not increase Nrf2 protein expression or cause its nuclear accumulation. However, pre-treatment with BSO triggered mRNA expression of HO-1 and GCLC. Furthermore, BSO pre-treatment suppressed DM-induced Nrf2 upregulation and activation and lowered mRNA expression of HO-1 and GCLC upon DM treatment. These data demonstrate that GSH depletion is not necessary for the activation of Nrf2/ARE by DM in PC12 cells, and that GCLC and HO-1 expression can increase through other signalling pathways. KEY WORDS: BSO, DL-buthionine-[S,R]-sulfoximine, glutamate cysteine ligase catalytic subunit, GCLC, heme oxygenase, HO-1, pyrethroid insecticid