title: Effects of di-isononyl phthalate (DINP) on peroxisomal markers in the marmoset-DINP is not a peroxisome proliferator.
abstract: In the present study the systemic toxic potential of di-isononyl phthalate (DINP) was assessed in a 13-week study in marmosets. Particular attention was given to its potential for hepatic peroxisome proliferation. Three groups of four male and four female marmosets received DINP, by oral gavage administration, at dosages of 100, 500 or 2500 mg/kg/day for 13 weeks. A fourth group served as a concurrent Control group and received the vehicle (1% methylcellulose and 0.5% Tween) only. A fifth group received clofibrate at a dosage of 500 mg/kg/day to provide a positive Control for liver peroxisome activity. At the end of the treatment period, the animals were killed and their livers were removed. 3000 x g supernatant and microsomal subcellular fractions were prepared from homogenised liver by differential centrifugation. The peroxisomal marker enzyme activity, cyanide-insensitive palmitoyl CoA oxidase, was assayed in the former, while cytochrome P450 concentration and lauric acid 11- and 12-hydroxylase activities (selective for CYP2E1 and 4A, respectively) were assayed in the microsomes. No statistically significant changes were seen in any of these parameters measured following DINP treatment, compared with the Control. Clofibrate treatment resulted in an approximately 100% increase (p < 0.01) in both male and female marmoset cyanide-insensitive palmitoyl CoA oxidase activity and a similar increase (p < 0.05) in male (only) lauric acid 11-hydroxylase activity. No other changes were statistically significant at the 5% level. These data provide no evidence that DINP was acting as a peroxisome proliferator when administered to marmosets under the conditions of the study.
authors.affiliation: Department of In Vitro Metabolism, Huntingdon Life Sciences Limited, England.
authors.forename: M
authors.initials: M
authors.lastname: Hall
authors.forename: A
authors.initials: A
authors.lastname: Matthews
authors.forename: L
authors.initials: L
authors.lastname: Webley
authors.forename: R
authors.initials: R
authors.lastname: Harling
mesh_terms: D000818:Animals; D015415:Biomarkers; D002144:Callithrix; D002458:Cell Fractionation; D002994:Clofibrate / Q000737:chemistry / Q000633:toxicity; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000737:chemistry / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000737:chemistry / Q000633:toxicity*; D010795:Phthalic Acids / Q000737:chemistry / Q000633:toxicity*; D012469:Salivary Glands / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; D020025:Peroxisome Proliferators; D010795:Phthalic Acids; C012125:diisononyl phthalate; D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A; C028427:palmitoyl CoA oxidase; D002994:Clofibrate