Search

The identification and subsequent characterization of preneoplastic lesions in different tissues, in animals subjected to chemical carcinogens and in man, gives rise to a new and attractive outlook in the prevention of cancer development. It might be possible, by modulating the promotion and progression steps of carcinogenesis to inhibit the development of preneoplastic tissue as well as its progression to neoplasia. The disappearance of preneoplastic lesions has been recently obtained after treatment with certain antioxidants, hypolipidemic drugs, dehydroepiandrosterone and some other related hormones1–5.

Absorbable hypolipidemic agents, mostly of the aryloxyacetic acid type, are still used most widely in the general clinical treatment of hyperlipidemia. These compounds will be, therefore, the major object of this presentation. Current hypotheses on the mode of action of these drugs will be analyzed in detail and, moreover, specific problems pertaining to their use will be discussed; among these peroxisomal proliferation, reporting new findings suggestive of specific structural features most and least likely to induce this effect. Finally, aiming to the specific interest of pharmacologists working in this area, the scope and validity of new experimental methodologies, e.g., activation of lipoprotein receptors and changes in high density lipoprotein (HDL) levels, will be examined.

It has recently been reported (1) that administration of the hypolipidemic drug clofibrate (ethyl-α-p- chlorophenoxyisobutyrate) to rats is followed by a great increase of the CoA-pool in their liver. The increase may amount to about 3-fold, and is mainly due to an increase of free CoA (1,2).

Investigation of the phenomenon of xenobiotic-induced peroxisome proliferation in liver parenchymal cells continues to provide fascinating details about the differential regulation of peroxisomal enzymes, their role in the production of intrahepatic oxidative stress and the possible relationship between sustained oxidative stress and the eventual development of hepatocellular carcinomas (1–3), Hepatic peroxisome proliferation was first noted nearly twenty years ago in the livers of rats treated with the hypolipidemic drug Clofibrate (4,5). Subsequently, several structurally diverse chemicals have been identified as hepatic peroxisome proliferators (1,2,6). Long-term feeding studies demonstrated the hepatocarcinogenicity of several of these agents (2,7–9), although they are not genotoxic in short-term tests (10–13). On the basis of these observations it was proposed that peroxisome proliferators form a novel class of chemical carcinogens (8), An understanding of the mechanism of induction of peroxisome proliferation and the metabolic events that accompany persistent increase in the number of these organelles is necessary to resolve the question whether these nongenotoxic hepatocarcinogenic peroxisome proliferators pose the same carcinogenic risk to humans as those that are genotoxic.

For fifteen years, we have been conducting numerous experiments on the induction of atherosclerosis in male Dutch belted rabbits, testing a variety of dietary fats and several hypolipidemic drugs. In all of these experiments, the standard atherogenic regimen that provided the basis for comparison of treatments was 2% cholesterol and 6% corn oil added to laboratory ration. Although each experiment contained its own control, we noted that the atheromata in the control rabbits varied from experiment to experiment. In an effort to ascertain a possible seasonal variation in atherosclerosis we have collated by month of autopsy data from 74 experimental identical 2-month feeding periods.

The inhibition of lipidemia can be achieved in several ways. The most logical mechanism — interference with lipoprotein metabolism (synthesis, release or catabolism) — has not been approached in a rational manner. There are some effective hypolipidemic drugs but their mechanisms of action are not clear and the search for a more effective compound continues.

The past 12 months have been an encouraging period for the development of new hypolipidemic agents. The Food and Drug Administration approved the drugs Probucol from Dow Chemical Company and Colestipol-HCl from Upjohn Company as official hypolipidemic agents.

Changes in plasma lipids and in lipoprotein distribution are well known consequences of the application of hypolipidemic drug regimens. In particular, VLDL lipids decrease with concomitant transient or permanent LDL cholesterol increases (Carlson et al. 1977); according to some reports also HDL cholesterol levels may increase following clofibrate (Wallentin 1978) or nicotinic acid treatments (Blum et al. 1977). Newer clofibrate derivatives appear more likely to increase HDL cholesterol (Olsson and Lang, 1978).

Drug treatment of hyperlipidemia has advanced markedly over the last two decades. Whereas earlier efforts were aimed at reduction of either cholesterol or triglyceride levels (usually the former), today drugs are tested for their effects on specific types of hyperlipidemia and on enrichment or depletion of specific lipoprotein fractions.

The effects of pharmacological agents on bile acid metabolism may be assessed in several ways. The total excretion of bile acids in the bile or feces can be measured, the spectrum of bile acids or their conjugates can be determined, or the synthesis of bile acids can be assessed. To date, most experimental approaches have involved the first of these possibilities.

Insight into the mechanism of action and efficacy of hypolipidemic drugs has awaited the development of the current concepts of lipid transport (1). Fundamental is the fact that the blood fats-- cholesterol, phospholipid, and triglyceride-- do not circulate free in the plasma. Lipids exist in a soluble form in the blood only because they are bound to protein. These proteins serve as detergents and solubilize the otherwise insoluble lipid. It is as lipid protein complexes or lipoproteins that all fat enters and leaves the blood stream.