Modification of lipoperoxidative effects of dichloroacetate and trichloroacetate is associated with peroxisome proliferation.
Pretreatment of male B6C3F1 mice with clofibric acid (CFA) or trichloroacetic acid (TCA) in the drinking water results in a marked decrease in the lipoperoxidative response as measured by the production of thiobarbituric acid reactive substances (TBARS) in mouse liver homogenates following acute dosing with TCA or dichloroacetic acid (DCA). Pretreatment with TCA or CFA also increased palmitoyl-CoA oxidase activity, microsomal 12-(omega) hydroxylation of lauric acid and expression of P450 4A isoforms. At the doses utilized, DCA-pretreatment did not increase the level of P450 4A protein, or markers of peroxisome proliferation. However, DCA-pretreatment did result in enhanced levels of TBARS, following acute dosing with DCA, compared to controls. Pretreatment with DCA, TCA, or CFA did not alter p-nitrophenol hydroxylation (an assay specific for P450 2E1), and no increases in immunodetectable P450 2E1, 4A, 1A1/2, 2B1/2 or 3A1 protein were observed. Assays from CFA- and TCA-pretreated mice suggest that the reduction in the TBARS response seen in TCA-pretreated animals results from activities associated with peroxisome proliferation. This might result from the induction of systems efficient in scavenging of peroxide intermediates or detoxification of aldehyde by-products of lipid peroxidation.
Austin
E W
EW
Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman 99164-6510, USA.
Okita
J R
JR
Okita
R T
RT
Larson
J L
JL
Bull
R J
RJ
D000818:Animals; D002374:Catalase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D014238:Trichloroacetic Acid / Q000633:toxicity*
D014238:Trichloroacetic Acid; D003577:Cytochrome P-450 Enzyme System; D003999:Dichloroacetic Acid; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D002374:Catalase; D042926:Cytochrome P-450 CYP4A; C028427:palmitoyl CoA oxidase