Characteristics of induction of peroxisomal fatty acid oxidation-related enzymes in rat liver by drugs. Relationships between structure and inducing activity.
To clarify the mechanism of induction of hepatic peroxisome-associated enzymes by drugs, we examined the interrelationship between the structures of fifteen drugs of two types (phenoxyacetic acid derivatives and perfluorinated compounds) and their inducing activities. Male Wistar rats were given the drugs at 150 mg/kg body weight daily for 2 weeks, and then hepatic activities of fatty acid metabolism-related enzymes were determined. The activity of the cyanide-insensitive fatty acyl-CoA oxidizing system located in peroxisomes was increased significantly in the following order: 2,4,5-trichlorophenoxypropionic acid (12.5-fold) greater than 2,4-dichlorophenoxypropionic acid (6.6-fold) greater than clofibrate (4.5-fold) greater than 2-methyl-4-chlorophenoxyacetic acid (2.6-fold) greater than 2,4,5-trichlorophenoxyacetic acid (2.5-fold) greater than p-chlorophenoxypropionic acid (2.4-fold) greater than 2,4-dichlorophenoxyacetic acid (1.7-fold). Treatment with perfluorinated compounds, perfluorobutyric acid, perfluorooctanoic acid, perfluorodecanoic acid and perfluorooctanol, also induced the activity by 2-, 4.3-, 3.1- and 2.0-fold respectively. The profile of the induction of carnitine acetyltransferase by these compounds was quite similar to that of cyanide-insensitive fatty acyl-CoA oxidizing system. Lipophilicity of these drugs was determined by the octanol-water partition method. Among these drugs, 2,4,5-trichlorophenoxypropionic acid showed the largest octanol/water partition coefficient (log P = 0.39). These results show a strong correlation among the number of chlor-substitutions on the phenyl moiety, the methyl-group on the alpha position of the acetic acid moiety, lipophilicity and the inducibility of peroxisomal fatty acid oxidation-related enzymes.
Kozuka
H
H
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Japan.
Yamada
J
J
Horie
S
S
Watanabe
T
T
Suga
T
T
Ikeda
T
T
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000032:analysis; D002374:Catalase / Q000032:analysis; D004790:Enzyme Induction; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010642:Phenoxyacetates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013329:Structure-Activity Relationship
D005227:Fatty Acids; D010642:Phenoxyacetates; D002374:Catalase; D002334:Carnitine O-Palmitoyltransferase