Role of Fatty Acyl Coenzyme A Oxidase in the Efflux of Oxidized Glutathione from Perfused Livers of Rats Treated with the Peroxisome Proliferator Nafenopin
1987
Abstract The diffusion of H 2 O 2 into the cytoplasm from peroxisomes during high rates of peroxisomal β 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 H 2 O 2 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 β-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 β-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 H 2 O 2 produced by fatty acyl coenzyme A oxidase during high rates of peroxisomal β-oxidation in livers from nafenopin-treated rats escapes detoxification by catalase and diffuses into the cytoplasm to be metabolized by glutathione peroxidase.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
21
Citations
NaN
KQI