1 The effects of hypolipidemic drugs fenofibrate (isopropyl[4-(p-chlorobenzoyl)-2-phenoxy-2-methyl]propionate), pyrinixil (BR-931; [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β-hydroxyethyl) acetamide]), methyl clofenapate (2-methyl-2[4-(p-chlorophenyl)phenoxy]2-methyl-propionate), and clofibrate (ethyl α-p-chloro-phenoxyisobutyrate) on plasma triglyceride levels, hepatic peroxisome proliferation and peroxisome-associated enzymes in hamsters were investigated.
2 Fenofibrate, pyrinixil and methyl clofenapate were administered in the diet at 0.2% level (w/w) for 6 weeks. Clofibrate was fed at 0.5% level.
3 Fenofibrate, pyrinixil and methyl clofenapate induced a marked proliferation of peroxisomes in hamster liver cells which was comparable to that observed in the rat and mouse liver, whereas the peroxisome proliferative effect of clofibrate was less pronounced. Peroxisomal fatty acid β-oxidation system was found in the hamster liver and its activity was enhanced significantly by hypolipidemic drugs. The magnitude of induction of [1-14C]palmitoyl CoA oxidation, heat-labile enoyl-CoA hydratase and peroxisome proliferation-associated 80000 mol. wt. polypeptide in the hamster appeared to parallel the extent of peroxisome proliferation.
4 All four hypolipidemic compounds increased hepatic catalase and carnitine acetyltransferase activities and decreased plasma triglyceride levels in the hamster. The observed hepatic effects of hypolipidemic drugs in hamster are identical to those induced by peroxisome proliferators in the rat and mouse.
5 These observations suggest that hypolipidemic agents identified as peroxisome proliferators in rats, mice and now hamsters would very likely enhance the peroxisomal enzyme system in other species. Additional information on the interspecies responses to peroxisome proliferators, however, is necessary to assess the role of peroxisome proliferation in carcinogenesis.
Get full access to this article
View all access options for this article.
References
1.
Allen, J. & Beard, M. (1965). α-Hydroxy acid oxidase: localization in renal microbodies. Science, 149, 1507-1509
2.
Beevers, H. (1969). Glyoxysomes of castor bean endosperm and their relation to gluconeo genesis. Ann. N.Y. Acad. Sci., 168, 313-324.
3.
Bronfman, M., Inestrosa, N.C. & Leighton, F. (1979). Fatty acid oxidation by human liver peroxisomes . Biochem. Biophys. Res. Commun., 88, 1030-1036.
4.
Deduve, C. & Baudhuin, P. (1966). Peroxisomes (microbodies) and related particles . Physiol. Rev., 46, 325-357.
5.
Hanefeld, M., Remner, C.H., Leonhardt, W. et al. (1980). Effects of p-chlorophenoxy isobutyric acid (CPIB) on the human liver. Atherosclerosis, 36, 159-172.
6.
Hess, R., Staubli, W. & Reiss, W. (1956). Nature of the hepatomegalic effect produced by ethyl-chlorophenoxyisobutyrate in the rat. Nature, 208, 856-858.
7.
Hurban, Z., Swift, H. & Slesers, A. (1966). Ultrastructural alterations of hepatic microbodies . Lab. Invest., 15, 1884-1901.
8.
Hurban, Z., Vigil, E., Slesers, A. & Hopkins, E. (1972). Microbodies. Constituent organelles of animal cells. Lab. Invest., 27, 184-191.
9.
Inestrosa, N.C., Bronfman, M. & Leighton, L. (1979). Detection of peroxisomal fatty acyl-CoA oxidase activity. Biochem. J., 182, 779-788.
10.
Ishii, H., Fukumori, N., Horie, S. & Suga, T. (1980). Effect of fat content in the diet on hepatic proxisomes of the rat. Biochim. Biophys. Acta, 617, 1-11.
11.
Ishii, H. & Suga, T. (1979). Clofibrate-like effects of acetylsalicylic acid on peroxisomes and on hepatic and serum triglyceride levels. Biochem. Pharmacol., 28, 2829-2833.
12.
Laemmli, U.K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 681-689.
13.
Lalwani, N.D., Reddy, M.K., Mark, M.M. & Reddy, J.K. (1981a). Induction, immunochemical identity and immunofluorescence localization of polypeptide PPA-80 and peroxisomal enoyl-CoA hydratase of mouse liver and renal cortex. Biochem. J., 198, 177 -186.
14.
Lalwani, N.D., Reddy, M.K., Qureshi, S.A. & Reddy, J.K. (1981b). Development of hepatocellular carcinomas and increased peroxisomal fatty acid β-oxidation in rats fed [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in the semi-purified diet. Carcinogenesis , 2, 645-650.
15.
Lazarow, P.B. (1977). Three hypolipidemic drugs increase hepatic palmitoyl-coenzyme A oxidation in the rat. Science, 197, 580-581.
16.
Lazarow, P.B. (1978). Rat liver peroxisomes catalyze the β-oxidation of fatty acids. J. Biol. Chem., 253, 1522-1528.
17.
Lee, K.J., Kim, D.N. & Lee, K.T. (1974). Ultrastructural study of hepatic mitochondrial abnormality in Swine treated with clofibrate. Exp. Mol. Pathol. , 20, 387-396.
18.
Lowry, O.H., Rosebrough, N.J., Farr, A.L. & Randall, R.J. (1951). Protein measurement with the falin phenol reagent . J. biol. Chem., 193, 265-275.
19.
Mannarts, G.P., Debeer, L.J., Thomas, J. & Deschepper, P.J. (1979). Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate treated rats. J. biol. Chem., 254, 4585-4595.
20.
Mcgraw, R.E., Dunn, D.E. & Biggs, H.G. (1979). Manual and continuous flow colorimetry of triglyceroles by a fully enzymic method. Clin. Chem., 25, 273-278.
21.
Moody, D.E. & Reddy, J.K. (1978a). Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds. Toxicol. appl. Pharmacol., 45, 497-504.
22.
Moody, D.E. & Reddy, J.K. (1978b). The hepatic effects of hypolipidemic drugs (clofibrate, nafenopin, tibric acid and Wy-14,643) on hepatic peroxisomes and peroxisome-associated enzymes. Am. J. Pathol., 90, 435.
23.
Neat, C.E., & Osmundson, H. (1979). The rapid preparation of peroxisomes from rat liver by using a vertical rotor. Biochem. J., 180, 445-448.
24.
Novikoff, A.B., Novikoff, P.M., Davis, C. & Quintana, J. (1973). Studies on microperoxisomes, V. Are microperoxisomes ubiquitous in mammalian cells? J. Histochem. Cytochem., 21, 737-755.
25.
Osumi, T. & Hashimoto, T. (1979a). Peroxisomal β-oxidation system of rat liver. Copurification of enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase . Biochem. biophys. Res. Commun., 89, 580-584.
26.
Osumi, T. & Hashimoto, T. (1979b). Occurrence of two 3-hydroxyacyl-CoA dehydragenase of rat liver. Biochem. Biophys. Acta, 574, 258-267.
27.
Reddy, J.K. (1973). Possible properties of microbodies (peroxisomes): microbody proliferation and hypolipidemic drugs. J. Histochem. Cytochem., 21, 967-974.
28.
Reddy, J.K. (1977). Induction of hepatic peroxisomes and peroxisome-associated enzymes: an evaluative test for hypolipidemic compounds. Proc. int. Conference on Atherosclerosis, Milan.
29.
Reddy, J.K. (1980). Hepatic peroxisome proliferative and carcinogenic effects of hypolipidemic drugs, in: Drugs affecting lipid metabolism , eds Fumagalli, F., Kritchevski, D. & Paoleti, R., pp.301-310. New York: Elsevier/North-Holland Biomedical Press.
30.
Reddy, J.K., Azarnoff, D.L. & Hignite, C.E. (1980). Hypolipidemic peroxisome proliferators form a novel class of chemical carcinogens. Nature, 283, 397-398.
31.
Reddy, J.K., Azarnoff, D.L. & Sirtori, C.R. (1978). Hepatic peroxisome proliferation: induction by BR-931, a hypolipidemic analog of Wy-14,643. Arch. int. Pharmacodyn. , 234, 4-14.
32.
Reddy, J.K., Azarnoff, D.L., Svoboda, D.J. & Prasad, J.D. (1974). Nafenopin-induced hepatic microbody (peroxisome) proliferation and catalase synthesis in rats and mice. J. Cell Biol., 61, 344-358.
33.
Reddy, J.K. & Krishnakantha, T.P. (1975). Hepatic peroxisome proliferation: induction by two novel compounds structurally unrelated to clofibrate. Science, 190, 787-789.
34.
Reddy, J.K. & Kumar, N.S. (1977). The peroxisome proliferation associated polypeptide in rat liver. Biochim. biophys. Res. Commun., 77, 824-829.
35.
Reddy, J.K. & Kumar, N.S. (1979). Stimulation of catalase synthesis and increase of carnitine acetyltransferase activity in the liver of intact female rats fed clofibrate. J. Biochem., 85, 847-856.
36.
Reddy, J.K., Lalwani, N.D., Reddy, M.K. & Qureshi, S.A. (1982). Excessive accumulation of autofluorescent lipofuscin in the liver during hepatocarcinogenesis by methyl clofenapate and other hypolipidemic peroxisome proliferators. Cancer Res., 42, 259-266.
37.
Reddy, J.K., Rao, M.S., Azarnoff, D.L. & Sell, S. (1979). Mitogenic and carcinogenic effects of a hypolipidemic peroxisome proliferators, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rat and mouse liver. Cancer Res., 39, 152.
38.
Reddy, J.K. & Warren, J.R. (1981). Toxicological implications of hepatic peroxisome: possible role of oxygen radical toxicity in hypolipidemic drug-induced carcinogenesis . Toxicologist, 1, 131 (abstract).
39.
Reddy, J. & Svoboda, D. (1971). Microbodies in experimentally altered cells, VIII. Continuities between microbodies and their possible biologic significance . Lab. Invest., 24, 74-81.
40.
Reddy, M.K., Hollenberg, P.F. & Reddy, J.K. (1980). Partial purification and immunoreactivity of an 80000 molecular weight polypeptide associated with perocisome proliferation in rat liver. Biochem. J., 188, 731-740.
41.
Reddy, M.K., Qureshi, S.A., Hollenberg, P.F. & Reddy, J.K. (1981). Immunochemical identity of peroxisomal enoyl-CoA hydratase with the peroxisome proliferation associated 80000 mol wt polypeptide in rat liver. J. Cell Biol., 89, 406-417.
42.
Steinman, H.M. & Hill, R.L. (1975). Bovine liver crotonase (enoyl-coenzyme A hyratase) . Methods Enzymol., 35, 136 -151.
43.
Svoboda, D.J. & Azarnoff, D.L. (1979). Tumors in male rats fed ethylchlorophenoxyisobutyrate, a hypolipidemic drug. Cancer Res., 39, 3419- 3428.
44.
Svoboda, D., Grady, H. & Azarnoff, D. (1967). Microbodies in experimentally altered cells. J. Cell Biol., 35, 127-152.
