MODIFICATION OF LIPOPEROXIDATIVE EFFECTS OF DICHLOROACETATE AND TRICHLOROACETATE IS ASSOCIATED WITH PEROXISOME PROLIFERATION

Pretreatment of male B6C3F(1) mice with clofibric acid (CFA) or trichl oroacetic acid (TCA) in the drinking water results in a marked decreas e in the lipoperoxidative response as measured by the production of th iobarbituric acid reactive substances (TEARS) in mouse liver homogenat es following acute dosing with TCA or dichloroacetic acid (DCA). Pretr eatment 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 incr ease the level of P450 4A protein, or markers of peroxisome proliferat ion. However, DCA-pretreatment did result in enhanced levels of TEARS, following acute dosing with DCA, compared to controls. Pretreatment w ith DCA, TCA, or CFA did not alter p-nitrophenol hydroxylation (an ass ay specific for P450 2E1), and no increases in immunodetectable P450 2 E1, 4A, 1A1/2, 2B1/2 or 3A1 protein were observed. Assays from CFA- an d TCA-pretreated mice suggest that the reduction in the TEARS response seen in TCA-pretreated animals results from activities associated wit h peroxisome proliferation. This might result from the induction of sy stems efficient in scavenging of peroxide intermediates or detoxificat ion of aldehyde by-products of lipid peroxidation.