Mixed-function oxidase system induction and propylene hepatotoxicity.
Propylene is hepatotoxic to male Charles River COBS Sprague-Dawley rats pretreated with polychlorinated biphenyls (PCB: Aroclor 1254). Four-hour inhalation exposure to 50,000 ppm propylene increased liver weight/body weight ratios and elevated serum enzyme activities in PCB-pretreated animals. Hepatic microsomal cytochrome P-450 content of PCB-pretreated rats dropped profoundly during propylene exposure and remained depressed for at least 24 h. In addition, PCB-pretreated, propylene-exposed rats exhibited a decrease in the specific activity of hepatic microsomal aniline hydroxylase. However, there was no change in activities of either hepatic microsomal aminopyrine demethylase or glucose-6-phosphatase. Propylene exposure of rats pretreated with beta-naphthoflavone (BNF), phenobarbital (PB), or a mixture of BNF and PB was not hepatotoxic. However, there was, in these animals, a substantial decline in hepatic microsomal cytochrome P-450 levels 24 h after the start of propylene exposure. Hence, the propylene-dependent process resulting in hepatic cytochrome P-450 destruction is qualitatively or quantitatively different from the process that causes acute hepatotoxicity. Preexposure fasting had no effect on the hepatotoxicity resulting from a 4-h exposure of PCB-pretreated rats to 50,000 ppm propylene. Administration of SKF-525A to PCB-pretreated rats immediately prior to propylene exposure completely prevented elevations in serum enzyme activities and liver weight/body weight ratios. In vitro incubation of hepatic microsomes prepared from either BNF-, PB-, or PCB-pretreated rats with an atmosphere of 20% propylene/80% air produced in NADPH-dependent decrease in cytochrome P-450 content. These results suggest that PCB pretreatment is a prerequisite for propylene hepatotoxicity in the rat. Cytochrome P-450-dependent bioactivation of propylene is associated with this hepatotoxicity, but further studies are needed to characterize the mechanism of the PCB-propylene interaction.
Osimitz
T G
TG
Conolly
R B
RB
D000475:Alkenes / Q000633:toxicity*; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000704:Analysis of Variance; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D001140:Aroclors / Q000633:toxicity; D001273:Atmosphere Exposure Chambers; D001571:Benzoflavones / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000096:biosynthesis*; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D000475:Alkenes; D001140:Aroclors; D001571:Benzoflavones; D020111:Chlorodiphenyl (54% Chlorine); D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C013658:propylene; D006899:Mixed Function Oxygenases; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D005952:Glucose-6-Phosphatase; D010634:Phenobarbital