title: Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenobarbital-induced promotion of hepatocarcinogenesis in rats by the type of diet and vitamin A deficiency.
abstract: This study was undertaken to investigate the influence of dietary vitamin A deficiency and type of diet on tetrachlorodibenzo-p-dioxin (TCDD)- and phenobarbital-induced liver tumor promotion in rats. Female Sprague-Dawley rats were partially hepatectomized and subsequently initiated with nitrosodiethylamine. One week later the rats were allocated to five different dietary regimens for the duration of the study: three purified (casein-based) diets containing 200, 1200, and 10000 IU vitamin A per kilogram, respectively, and two conventional (cereal-based) rat diets containing 2000 and 14000 IU vitamin A per kilogram, respectively. After an additional 4 weeks, groups of rats on each dietary regimen were started on one of four different promoter treatments: 0.07 micrograms TCDD/kg/week (sc); 0.7 micrograms TCDD/kg/week (sc); 500 ppm phenobarbital in the drinking water or vehicle only (arachis oil, sc). The study was terminated after 16 weeks of promoter treatment. Sections of liver were stained for gamma-glutamyltranspeptidase (GGT) activity and GGT-positive altered hepatic foci (AHF) were evaluated by stereological methods. All factors studied (TCDD, phenobarbital, dietary vitamin A content, and the type of diet) were shown to influence AHF development significantly. As expected, TCDD and phenobarbital enhanced foci development. Vitamin A deficiency enhanced foci development in its own right and increased the TCDD-induced response markedly. Dietary vitamin A content did not modulate phenobarbital promotion of AHF in the same manner. The enhancement of TCDD-induced effects on foci development by vitamin A deprivation was accompanied by an increased incidence of histological changes marking degeneration in the liver (e.g., oval cell hyperplasia) and accentuation of other TCDD-related toxic responses. In addition, the groups of rats maintained on the cereal-based diets and subjected to the various promoter/vitamin A regimens exhibited significantly higher AHF incidence as compared to correspondingly treated rats fed the purified, casein-based diets. In conclusion, vitamin A deficiency alone may promote hepatocarcinogenesis and enhance the promoting effect of TCDD treatment. However, TCDD-induced depletion of hepatic vitamin A stores was not implicated as a major cause of promotion by TCDD. Nevertheless, vitamin A deficiency brought about by TCDD alone may well act as a promotive stimulus concertedly with an as yet unidentified cellular mechanism in TCDD-induced liver tumor promotion. The differential effects of the two types of diets recorded in the study remain undocumented.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Flodström
authors.forename: L
authors.initials: L
authors.lastname: Busk
authors.forename: T
authors.initials: T
authors.lastname: Kronevi
authors.forename: U G
authors.initials: UG
authors.lastname: Ahlborg
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D005260:Female; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000517:prevention & control; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010634:Phenobarbital / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D000637:Transaminases / Q000097:blood; D014801:Vitamin A / Q000097:blood / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000503:physiopathology*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D014801:Vitamin A; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D000637:Transaminases; D010634:Phenobarbital