POTENTIAL FETOPROTECTANTS FROM ETOH-INDUCED STRESS

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The ingestion of EtOH can lead to the creation of a variety of free radical species. If EtOH consumption is heavy and chronic, organs within the body begin to deteriorate. Some of the organ damage sustained as a consequence of EtOH consumption might be caused by free radical generation and subsequent lipid peroxidation (LPO). It is now theorized that the pervasive and toxic effects of LPO may contribute to the expression of fetal alcohol syndrome (FAS). Silymarin (SY), a plant-derived flavone, has been identified as an effective antioxidant and is currently marketed in Europe wider the trade name Legalon(R) as a hepatoprotective medication. We have conducted several animal studies of the hepatoprotective and fetoprotective effects of SY against EtOH-induced enzyme activity in maternal and fetal brain and liver tissue. We now want to test the antioxidant effects of SY and four other antioxidant flavonoids; quercetin, myricetin, (+)-catechin, and apigenin on EtOH-exposed fetal rat brain and liver tissue. Testing of the additional bioflavonoid compounds is predicated on the results of studies in which it was demonstrated that these flavonoids also inhibited EtOH-induced free radical production. For purposes of comparison of antioxidant efficacy, N-acetylcysteine (NAC) and S- adenosylmethione (SAM) will also be tested. It has been demonstrated in previous in vitro studies that the incubation of fetal rat hepatocyte (FRH) mitochondria in EtOH increased indications of oxidative stress. It was further established that the treatment of the FRH mitochondria with NAC or SAM before and during the 24-hr exposure to EtOH prevented the decrease in glutathione (GSH), restored cell replication, and moderated malondialdehyde (MDA) production. We will extend this in vitro model to an in vivo model to test the general hypothesis that one or all of the flavonoids will be as effective as NAC or SAM at normalizing Et0H-induced oxidative stress in fetal brain and liver tissue. Dams will be intubated with EtOH six times at 12-hr. intervals over days 12, 13, and 14 of gestation following the procedures described in Henderson, Devi, Perez, & Schencker (1995). The dependent measures used to assess outcome will be: fetal viability, fetal weight, liver histology, fetal brain and liver tissue glutathione levels, alpha tocopherol levels, MDA levels, and GGTP activity. In addition, to continue with current studies in our lab, we will establish parallel groups in which rat pups will be raised for subsequent behavioral testing.