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  • Title: Phenobarbital-induced cytosolic cytoprotective mechanisms that offset increases in NADPH cytochrome P450 reductase activity in menadione-mediated cytotoxicity.
    Author: Utley WS, Mehendale HM.
    Journal: Toxicol Appl Pharmacol; 1989 Jun 15; 99(2):323-33. PubMed ID: 2544042.
    Abstract:
    Hepatocytes isolated from phenobarbital (PB)-pretreated and naive male Sprague-Dawley rats were incubated with menadione under one of three oxygen conditions (0, 21, or 95% oxygen) for 3 hr. During this time, samples were drawn and assayed for lactate dehydrogenase release and trypan blue exclusion as indices of cytotoxicity. Neither parameter indicated any significant difference in menadione-induced cytotoxicity between naive and PB-pretreated hepatocytes. Likewise, no difference was observed between hepatocytes incubated in 21% versus 95% O2. Consistent with the oxyradical hypothesis of menadione-induced cytotoxicity, hepatocytes incubated under 0% O2 (95:5; N2:CO2) did not exhibit any menadione cytotoxicity. Hepatic microsomes prepared from PB-pretreated rats exhibited a threefold increase in NADPH cytochrome P450 reductase activity over those of controls. Menadione-stimulated superoxide (O2-) production was twofold higher in PB pretreated versus naive liver microsomes. However, PB pretreatment failed to produce an increase in O2- production in intact hepatocytes or in hepatocytes disrupted by sonication. The failure of PB pretreatment to increase menadione-induced cytotoxicity and superoxide production in either intact or sonicated hepatocytes suggests that a concomitant cytoprotective mechanism is induced as well. The data further indicate that the cytoprotective elements are located in a nonmicrosomal fraction of the cell. In support of this, we observed PB-induced increases in glutathione levels, glutathione reductase, and DT-diaphorase activities. These findings indicate that PB-induced enhancements of the hepatocellular cytoprotective mechanisms collectively compensate for the increased redox cycling mechanism, resulting in a mitigation of the anticipated increased hepatocellular cytotoxicity of menadione.
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