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Role of Fatty Acyl Coenzyme A Oxidase in the Efflux of Oxidized Glutathione from Perfused Livers of Rats Treated with the Peroxisome Proliferator Nafenopin

Department of Experimental Pathology and Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

The diffusion of H₂O₂ into the cytoplasm from peroxisomes during high rates of peroxisomal ß oxidation of fatty acids was studied in perfused livers from rats treated with the hepatocarcinogenic peroxisome proliferator, nafenopin. Efflux of oxidized glutathione (GSSG) into the bile was used as a measure of increased H₂O₂ supply for cytoplasmic glutathione peroxidase. Male F-344 rats were given methylcellulose vehicle or nafenopin (80 mg/kg/day) by gavage for 5–8 days and livers perfused in situ with Krebs-Henseleit buffer containing 50 µM taurocholate and 0.75 g/100 ml albumin. In livers from fed, vehicle-treated or fed, nafenopin-treated rats basal rates of GSSG efflux were about 60 nmol/g/h. Subsequent infusion of 350 µM lauric acid, an excellent substrate for peroxisomal ß-oxidation, had no effect on GSSG efflux. To maximize fatty acid oxidation rats were fasted 16–20 h. In livers from fasted, nafenopin-treated rats the basal rate of GSSG efflux was 384 ± 85 (SE) nmol/g/h (n = 8). Subsequent infusion of lauric acid increased the rate to 940 ± 138 nmol/g/h. In livers from fasted, vehicle-treated rats lauric acid caused GSSG efflux to increase slightly from 104 ± 14 to 286 ± 37 nmol/g/h (n = 9). Efflux of reduced glutathione in bile was similar in livers from fasted, vehicle-treated (163 ± 15 nmol/g/h) and fasted, nafenopin-treated rats (135 ± 17 nmol/g/h) and decreased about 30% with lauric acid infusion. N-Octanoyl and oleoyl coenzyme A were excellent substrates for cyanide-insensitive NAD⁺ reduction in liver homogenates from fasted, nafenopin-treated rats whereas n-butyl, linoleoyl, and arachidonyl coenzyme A were poor substrates. Infusion of octanoate and oleate caused large increases in GSSG efflux from perfused livers from fasted, nafenopin-treated rats. In contrast, butyrate, linoleate, and arachidonate had no effect on GSSG efflux from livers from fasted, nafenopin-treated rats. Octanoate, oleate, linoleate, butyrate, and arachidonate had no effect on GSSG efflux from livers from fasted, vehicle-treated rats. Infusion of 2-bromooctanoate (600 µM) completely blocked lauric acid-induced increases in GSSG efflux and acetoacetate and ß-hydroxybutyrate production in livers from fasted, nafenopin-treated rats. Infusion of 1-3-bis(2-chloroethyl)-1-nitrosourea reduced glutathione reductase activity by 90% but did not alter lauric acid-induced increases in GSSG efflux or ketogenesis in livers from fasted, nafenopin-treated rats. The data suggest that some H₂O₂ produced by fatty acyl coenzyme A oxidase during high rates of peroxisomal ß-oxidation in livers from nafenopin-treated rats escapes detoxification by catalase and diffuses into the cytoplasm to be metabolized by glutathione peroxidase.

¹ To whom requests for reprints should be addressed, at CIIT, P.O. Box 12137, Research Triangle Park, NC 27709.

Received 3/16/87. Revised 6/ 8/87. Accepted 6/11/87.

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