Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643.
Quantitative comparisons of the time course of biochemical and morphological changes induced by peroxisome proliferators resulting in low and high incidences of hepatic cancer have not been conducted previously under bioassay conditions. [4-Chloro-6-(2,3-xylidino)-2-pyrimidyl-thio]acetic acid (Wy-14,643) at 0.1% in the diet produced a much higher incidence of hepatic cancer in male rats than 1.2% di(2-ethylhexyl)phthalate (DEHP) in the diet. Both diets, however, caused similar degrees of peroxisome proliferation. To investigate this difference in carcinogenicity, H2O2-detoxification mechanisms and indices of oxidative damage were evaluated in male F-344 rats fed 1.2% DEHP or 0.1% Wy-14,643 for up to one year. DEHP or Wy-14,643 treatment increased hepatic catalase activity approximately 25% from 8 to 365 days. DEHP or Wy-14,643 treatment decreased hepatic glutathione peroxidase activity by 50% from 8 to 365 days. Glutathione concentrations were not affected by 151 days of DEHP or Wy-14,643 feeding. The similar effects of DEHP and Wy on H2O2 detoxification enzymes and glutathione concentrations suggests that these factors are not responsible for the widely different carcinogenicities of Wy-14,643 and DEHP. Hepatic vitamin E concentrations were 50% lower in rats receiving Wy-14,643 for 151 days as compared to rats fed DEHP or control diets. Lipofuscin, which was contained within lysosomes, was increased 3-fold after 39 days of DEHP and remained at this level up to 365 days of treatment. In comparison, lipofuscin was increased 4-fold after 18 days of Wy-14,643 and continued to accumulate in a linear manner reaching values 30-fold over controls after 365 days of treatment. DEHP treatment for 39-365 days increased the activities of the lysosomal enzymes alpha-fucosidase, beta-galactosidase and N-acetylglucosaminidase 50-100%. The same enzyme activities were increased approximately 4-fold after 39-365 days of Wy-14,643. Lysosomal cathepsin B activity was unchanged by DEHP but doubled by 151 and 365 days of Wy-14,643. Acid phosphatase activity was unchanged by DEHP but increased by 50% after 151 and 365 days of Wy-14,643. In addition, conjugated dienes were increased (approximately 45%) only in rats receiving Wy-14,643 for 151 and 365 days. These data show for the first time that the magnitude and time course of lipofuscin deposition, induction of lysosomal enzymes and conjugated diene accumulation, is correlated closely with the degree of carcinogenicity. Wy-14,643-induced decreases in hepatic vitamin E concentrations could contribute to the observed accumulation of conjugated dienes at later time points.(ABSTRACT TRUNCATED AT 400 WORDS)
Conway
J G
JG
Chemical Industry Institute of Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Tomaszewski
K E
KE
Olson
M J
MJ
Cattley
R C
RC
Marsman
D S
DS
Popp
J A
JA
D000818:Animals; D000924:Anticholesteremic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008062:Lipofuscin / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D010084:Oxidation-Reduction; D010795:Phthalic Acids / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014810:Vitamin E / Q000502:physiology
D000924:Anticholesteremic Agents; D008062:Lipofuscin; D010795:Phthalic Acids; D011743:Pyrimidines; D014810:Vitamin E; C006253:pirinixic acid; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate