Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens

Abstract

Several drugs, including clofibrate (ethyl-a-p-chlorophenoxyisobutyrate)¹, are now available for the treatment of hyperlipidaemias^2,3 and others are in the process of preclinical or clinical evaluation^4,5. Clofibrate, the most widely used hypo-lipidaemic drug in Europe and the US², as well as other potent hypolipidaemic agents, cause massive hepatomegaly when administered to rats^6–8, mice^7,8 or hamsters (J.K.R., unpublished). This hepatomegaly is characteristically associated with a marked increase of peroxisomes (Fig. 1) in the liver cells of all three species^6–8. These ubiquitous cytoplasmic organelles^9,10contain catalase, several hydrogen peroxide-generating oxi-dases, carnitine acetyltransferase¹¹ as well as enzymes involved in the β-oxidation of long-chain fatty acids¹². The activities of these enzymes in liver are elevated in association with peroxisome proliferation^8,13. As hepatomegaly and peroxisome proliferation persist for as long as these drugs are administered to the animals, we initiated chronic toxicity studies with selected hepatic peroxisome proliferators in CS^b mice and F344 rats. Liver tumours were observed in both rats and mice fed nafeno-pin (2-methyl-2[p-(l,2,3,4-tetrahydro-l-naphthyl)phenoxy]-propionic acid)^14–16 or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid)¹⁷, two structurally unrelated compounds (Fig. 2, compounds 2 and 3) which are several times more potent than clofibrate in inducing peroxisome proliferation and hypolipidaemia⁸. Recent evidence indicates that clofibrate (Fig. 2, compound 1) is also carcinogenic when fed to rats at a concentration of 0.5% in the diet^18,19. We report here that BR-931 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β-hydroxyethyl)-acetamide])²⁰ and tibric acid(2-chloro-5-(3,5-dimethylpiperidinosulphonyl)benzoic acid)⁸, two potent hypolipidaemic hepatic peroxisome proliferators (Fig. 2, compounds 4 and 5) induce hepatocellular carcinomas in CS^b mice and/or F344 rats. Thus, the development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds (Fig. 2) supports our hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.