Role of Nrf2 and ARE family during EtOH-mediated oxidative modulation of DCLF-induced hepato- and nephrotoxicity.

摘要

Maintenance of cellular homeostasis during drug-induced oxidative stress (OS) resides in transcriptional activation or induction of antioxidant genes that are Nrf2 dependent. Nrf2 is sensitive to reactive oxygen species which drive potentiation reactions. We examined Nrf2 expression and its possible links to OS and OS-sensitive pro- and anti-apoptotic genes during EtOH potentiated DCLF-induced hepato- and nephrotoxicity. Female ICR mice were fed EtOH containing drinking water (3 to 6% for 4 wks. with normal chow) followed by DCLF (150 mg/kg, po) on day 28. Mice were sacrificed 24 hrs later. Blood was collected for serum chemistry, and the liver and kidneys for tissue biochemistry and western blot analysis. Data indicated that EtOH exposure increased DCLF-induced nephrotoxicity in the absence of significant hepatotoxicity. Gene expression analysis revealed increased expression of Nrf2 in EtOH, DCLF and EtOH+DCLF exposed organs consistent with proportionate increases in serum ALT, BUN, DNA fragmentation and OS. Histopathology disclosed increased incidence of apoptosis and necrosis consistent with changes in expression of bad/bax/bid coupled with decreased expression of bcl-xL in EtOH+DCLF exposure. Induction of CYP450 isozymes has been considered the key to EtOH-potentiated xenobiotic-mediated organ toxicity, there may be other mechanisms at the genetic level that can influence potentiation reactions.