Inhibition instead of enhancement of lipid peroxidation by pretreatment with the carcinogenic peroxisome proliferator nafenopin in rat liver exposed to a high single dose of corn oil.
Oxidative stress is discussed as a possible hepatocarcinogenic mechanism of peroxisome proliferators (PP) in rodents and is suggested to result from the induction of peroxisomal beta-oxidation (PBOX) by PP. The induced PBOX is assumed to produce excessive H2O2 from the degradation of fatty acids, ultimately leading to oxidative stress and lipid peroxidation. In the present short term-study, we attempted to stimulate lipid peroxidation in male Wistar rats by (1) inducing PBOX enzymes with the peroxisome proliferator nafenopin at 90 mg/kg body weight per day in the diet for 10-11 days, and (2) by supplying the induced PBOX with an abundant amount of fatty acid as substrate, using a corn oil gavage at 20 ml/kg body weight. The corn-oil gavage alone, i.e. without preceding nafenopin treatment, enhanced liver triacylglycerol nine- to tenfold and hepatic lipid peroxidation, measured as thiobarbituric acid reactive substances (TBARS), was increased 50% compared with controls. Both observations were made after 18 h when the peak elevations occurred. Upon pretreatment with nafenopin, associated with a sevenfold induction of PBOX, the corn oil gavage however caused only a threefold maximal increase in hepatic triacylglycerol, also at the 18 h time-point; TBARS remained almost at control levels, as monitored at seven time points over 24-25 h. These results suggest that nafenopin reduces rather than enhances lipid peroxidation, despite the provision, in a short term study, of high doses of substrate to the induced enzyme system that is hypothetically causing oxidative stress in the liver.
Huber
W W
WW
Institut für Tumorbiologie-Krebsforschung, Vienna, Austria.
Grasl-Kraupp
B
B
Stekel
H
H
Gschwentner
C
C
Lang
H
H
Schulte-Hermann
R
R
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism; D003314:Corn Oil; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D009255:Nafenopin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000032:analysis
D002273:Carcinogens; D014280:Triglycerides; D009255:Nafenopin; D003314:Corn Oil; D002332:Carnitine O-Acetyltransferase