Effect of hypolipidemic compounds on lauric acid hydroxylation and phase II enzymes.
Treatment of male Fischer 344 rats with various hypolipidemic drugs of different peroxisome proliferating potency (1-benzylimidazole, acetylsalicylic acid, clofibrate, tiadenol) led to an induction of liver lauric acid hydroxylase, whereas probucol, which is not a peroxisome proliferator, did not induce this enzyme. Activity of bilirubin UDP-glucuronosyltransferase was increased by all the compounds tested. The highest increase was observed after treatment with acetylsalicylic acid (2.3-fold). High correlation (r = 0.953) was observed between the activities of lauric acid hydroxylase and the corresponding activities of cytosolic epoxide hydrolase reported previously. The amount of microsomal epoxide hydrolase was not changed by any of the compounds. Whereas clofibrate and tiadenol decreased glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene as substrate, 1-benzylimidazole and probucol increased this activity. With 4-hydroxynonenal as a substrate qualitatively the same results were obtained with the exception that probucol did not affect the enzyme activity. When glutathione S-transferase activity was measured with cis-stilbene oxide as substrate only the more than five-fold increase after treatment with 1-benzylimidazole was significantly different from control values. Activity of dihydrodiol dehydrogenase was increased after treatment of rats with 1-benzylimidazole (1.5-fold), whereas application of tiadenol led to a decrease of enzyme activity. Feeding of male guinea pigs with clofibrate did not change the activity of peroxisomal beta-oxidation, cytosolic epoxide hydrolase or lauric acid hydroxylase. However, treatment with tiadenol caused an increase of these activities.
Thomas
H
H
Institut für Toxikologie, Mainz, Federal Republic of Germany.
Schladt
L
L
Knehr
M
M
Post
K
K
Oesch
F
F
Boiteux-Antoine
A F
AF
Fournel-Gigleux
S
S
Magdalou
J
J
Siest
G
G
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006168:Guinea Pigs; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008830:Microbodies / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D005233:Fatty Alcohols; D000960:Hypolipidemic Agents; D007093:Imidazoles; C004568:tiadenol; C017062:1-benzylimidazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; D002994:Clofibrate; D001241:Aspirin