Peroxisome proliferators, administration

Tamura, H.. lida. T.. Watanabe, T. Suga, T. (1990) Long-term effects of hypolipidemic peroxisome proliferator administration on hepatic hydrogen peroxide metabolism in rats. Carcinogenesis, 11,445-450... 

Repeated administrations of TCA induced cell proliferation in the livers of mice but reduced cell proliferation in the livers of rats. It causes hepatic peroxisome proliferation in both rats and mice but not humans."... 

Hepatic peroxisome proliferation depends on a nuclear receptor, PPARa, to mediate these responses in mice, based on lack of response to peroxisome proliferators in PPARa-deficient mice. In one study with another peroxisome proliferator, WY-14,643, carcinogenesis was shown to be dependent on the same receptor. Oral administration of di(2-ethylhexyl) phthalate failed to elicit markers of peroxisome proliferation in PPARa-deficient mice, while the same treatment elicited this response in normal mice. Metabolites of di(2-ethylhexyl) phthalate caused activation of PPARa-mediated gene expression in mammalian cell co-transfection assays. Differences between responsive rodents and humans in various aspects of PPARa-mediated regulation of gene expression are consistent with the lack of activity of di(2-ethylhexyl) phthalate metabolites in hepatocyte cultures from 12 people studied to date. 

Tamura,H., lida, T, Watanabe, T. Suga,T. (1991) Lack of induction of hepatic DNA damage on long-term administration of peroxisome proliferators in male F-344 rats. Toxicologist, 69, 55-62... 

Kawashima, Y., Nakagawa, S., Tachibana, Y. Kozuka, H. (1983a) Effects of peroxisome proliferators on fatty acid-binding protein in rat liver. Biochim. biophys. Acta, 754, 21-27 Kawashima, Y, Hanioka, N., Matsumura, M. Kozuka, H. (1983b) Induction of microsomal stearoyl-CoA desaturation by the administration of various peroxisome proliferators. 

Chronic administration of peroxisome proliferators to rodents results in sustained oxidative stress due to overproduction of peroxisomal hydrogen peroxide. The induction of peroxisomal fatty acid P-oxidation by cinnamyl anthranilate in vivo under bioassay conditions (Lake et al, 1997) supports this h othesis. Other data on the induction of oxidative stress are not available for cinnamyl anthranilate. 

Cinnamyl anthranilate has the characteristic effects of a peroxisome proliferator on mouse liver, increasing the activity of peroxisomal fatty acid-metabolizing enzymes and microsomal CYP4A and increasing hepatocellular proliferation. These effects are mediated by the intact ester, and were not seen after administration of the hydrolysis products, cinnamyl alcohol and anthranilic acid. The corresponding effects on rat liver were very much weaker. No relevant data from humans were available. 

FDA. 1990. The relationship between carcinogenesis and peroxisome proliferation in rodent liver after exposure to the plasticizer DEHP and DEHA. U. S. Food and Dmg Administration. 

Currently, over 100 compounds have been identified as PPs. The literature indicates that induction of peroxisome proliferation is not limited to exogenous chemicals. A number of endogenous substances, such as the steroid hormones, thyroid hormones, mor-phogenes, and fatty acids, are also involved in peroxisome proliferation. Peroxisome proliferation in hepatic parenchymal cells of rats and mice following the administration of clofibrate has been reported by numerous investigators. Compounds that are structurally unrelated to clofibrate, such as acetaminophen and Wy-14,643, can also cause peroxisome proliferation (Table 1). The industrial solvent trichloroethylene, the industrial plasticizers dill-ethyl hexyl) phthalate (DEHP) and di(2-ethyl hexyl) adipate (DEHA), have also been found to be hepatic peroxisome proliferators. 

Peroxisomes are subcellular organelles found in the cytoplasm of mammalian cells that carry out important metabolic functions (de Duve 1996 Hashimoto 1996 Mannaerts and van Veldhoven 1996). Under a variety of altered physiological and metabolic states, peroxisomes are known to proliferate, most notably with increased concentrations of unsaturated and polyunsaturated fatty acids. Interest in the toxicology community was piqued when peroxisome proliferation was noted in rodent hepatocytes in response to the administration of certain xenobiotics (e.g., Hess et al. 1965 Reddy and Chu 1996 Reddy and Rao 1977). Based on the association between exposure and peroxisome proliferation, the chemical and pharmaceutical agents that induce this response have been collectively referred to as peroxisome proliferators. ... 

---