title: Comparison of the effects of cinnamyl anthranilate on hepatic peroxisome proliferation and cell replication in the rat and mouse.
abstract: The effects of cinnamyl anthranilate (CA) have been compared in female B6C3F1 mice and female F344 rats fed diets containing 0-3.0% CA for periods of 1, 4, and 13 weeks. In the mouse, treatment with CA at all time points produced a marked dose-dependent increase in relative liver weight and hepatic peroxisome proliferation as demonstrated by the induction of peroxisomal (cyanide-insensitive palmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty acid oxidizing enzyme activities. CA produced only small increases in relative liver weight and palmitoyl-CoA oxidation in the rat and did not induce lauric acid 12-hydroxylase activity. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine during Study Weeks 0-1, 3-4, and 12-13. After 1 week of CA treatment, labeling index values were increased in rat and to a greater extent in mouse hepatocytes. While CA treatment for 4 and 13 weeks did not increase hepatocyte-labeling index values in the rat, a sustained stimulation of replicative DNA synthesis was observed at some dietary levels in the mouse. These results demonstrate a marked species difference between the hepatic effects of CA in female B6C3F1 mice and female F344 rats. While CA is a potent peroxisome proliferator in the mouse, it is only a very weak agent in the rat. The formation of liver tumors in long-term studies, at high doses of CA, appears to be attributable to a sustained stimulation of both peroxisome proliferation and cell replication in mouse hepatocytes.
authors.affiliation: BIBRA International, Woodmansterne Road, Carshalton, Surrey, SM5 4DS, England.
authors.forename: B G
authors.initials: BG
authors.lastname: Lake
authors.forename: R J
authors.initials: RJ
authors.lastname: Price
authors.forename: M E
authors.initials: ME
authors.lastname: Cunninghame
authors.forename: D G
authors.initials: DG
authors.lastname: Walters
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005421:Flavoring Agents / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008830:Microbodies / Q000187:drug effects*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D005421:Flavoring Agents; D062367:ortho-Aminobenzoates; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; C007068:cinnamyl anthranilate