Permethrin, a pyrethroid insecticide, regulates ERK1/2 activation through membrane depolarization-mediated pathway in HepG2 hepatocytes

Permethrin is a pyrethroid insecticide that acts thru membrane depolarization and is known to disrupt calcium levels in neurons. Disrupted calcium homeostasis is linked to oxidative stress as well as many other cellular mis-functions and permethrin has been reported to disrupt lipid and glucose metabolism in animals and mammalian cell models. It is not known, however, if permethrin influences calcium levels and its associated cellular mechanisms in liver cells. Thus, the goal of the current study was to investigate the mechanisms of permethrin on calcium-mediated cellular signaling pathway, particularly on activation of extracellular signal-related kinase (ERK1/2 or p42/p44) using human hepatocytes, HepG2. The current results showed that permethrin treatment induced oxidative stress and phosphorylation of ERK1/2, which were dependent upon voltage-sensitive sodium channels (VSSC). It was further determined that permethrin-induced ERK1/2 activation was mediated by the metabotropic glutamate receptors (mGluRs)-phosphoinositide phospholipase C (PLC)-protein kinase C (PKC) pathway, but not by changes of intracellular calcium or ER stress-mediated mechanisms.