Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid beta-oxidation pathway in the rat by clofibrate and di-(2-ethylhexyl)phthalate. Dose-response studies.
Male Wistar rats have been pretreated with either clofibrate or diethylhexylphthalate and the dose-dependency of induction of the microsomal, cytochrome P-452-driven fatty acid hydroxylase and peroxisomal fatty acid beta-oxidation system investigated. Both clofibrate and DEHP specifically induced (approximately 10-fold) the 12-hydroxylation of lauric acid in a dose-dependent manner and only marginally increased the associated 11-hydroxylase activity. This dose-dependent increase in fatty acid hydroxylase activity was accompanied by a similar ten-fold increase in the specific content of the cytochrome P-452 isoenzyme responsible for this activity, as assessed by an immunochemical-based ELISA method. Similarly, both clofibrate and DEHP induced the peroxisomal fatty acid beta-oxidation pathway in a dose-dependent manner. Furthermore, our results provide evidence that, after oral administration, clofibrate has a higher in vivo potency in inducing the above enzymes of fatty acid metabolism than is exhibited by DEHP. A correlation matrix analysis of the above data indicated a close association between the induction of microsomal cytochrome P-452 (and its associated fatty acid hydroxylase activity) and peroxisomal beta-oxidation enzymes, implicating a mechanistic inter-relationship between changes in fatty acid metabolising enzymes in these two hepatic subcellular organelles.
Sharma
R
R
University of Surrey, Department of Biochemistry, Guildford, U.K.
Lake
B G
BG
Gibson
G G
GG
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D003580:Cytochromes / Q000096:biosynthesis*; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D010795:Phthalic Acids / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D003580:Cytochromes; D005227:Fatty Acids; D010795:Phthalic Acids; C046362:cytochrome P-452; D004051:Diethylhexyl Phthalate; D002994:Clofibrate