Specificity in the action of hypolipidemic drugs: increase of peroxisomal ,&oxidation largely dissociated from hepatomegaly and peroxisome proliferation

Hypolipidemic drugs increased 3to 4-fold the activity of the peroxisomal &oxidation system in rat liver, with modest or no effects on catalase activity, liver weight, or peroxisome abundance. This specificity of action was observed in two experimental models: 7) bezafibrate treatment of male rats (25 mg/kg body wt., p.0.) and 2) clofibrate treatment of female rats (5 g/kg chow). Bezafibrate had no effect on the liver content of protein, catalase, or cytochrome oxidase, and little or no effect on mitochondrial &oxidation. The results indicate that the hypotriglyceridemic mechanism of action of these drugs involves an induction of the peroxisomal B-oxidation system, but this mechanism does not obligatorily include gross hepatomegaly or other alterations of peroxisomes that are often caused by hypolipidemic compounds. This dissociation of specific biochemical changes from other effects demonstrates a precise regulation of organelle biogenesis. Peroxisomes synthesized under the influence of bezafibrate or clofibrate have a different enzymatic composition than do normal peroxisomes.l These results have several implications. 7) Side effects of clofibrate that are of current clinical concern may be unrelated to its lipid-lowering effects. 2) Measurement of peroxisomal &oxidation should be a sensitive and specific tool for screening for new hypotriglyceridemic compounds. 3) Peroxisome proliferation or lack thereof is not central to efficacy. 4) Other new drugs may be discovered that are highly discriminating in elevating specific enzymes of fatty acid catabolism while causing even less or no hepatomegaly and other side effects.-Lazarow, P. B., H. Shio, and M. A. Leroy-Houyet. Specificity in the action of hypolipidemic drugs: increase of peroxisomal &oxidation largely dissociated from hepatomegaly and peroxisome proliferation in the rat. J . Lipid Res. 1982. 23: 317-326. Supplementary key words mitochondria bezafibrate clofibrate serum lipids hepatic fatty acid oxidation cell fractionation morphometry of fatty acids in rat liver: the familiar mitochondrial system, and the peroxisomal system that we have described (1, 2). The peroxisomal system has also been detected in human liver (3). The activity of the peroxisomal poxidation system in male rats is increased one order of magnitude by the hypolipidemic drugs, clofibrate,* tibric acid,3 and W ~ 1 4 , 6 4 3 ~ (1, 4), leading us to infer that increased peroxisomal P-oxidation plays an important role in the hypotriglyceridemic mechanism of action of these compounds (4, 5). The three drugs mentioned above, as well as many analogs of clofibrate, also cause proliferation of hepatic peroxisomes, an increase in the activity of catalase (a major peroxisomal enzyme (6)), and an increase in liver weight (7-16). These latter effects, which are not necessarily desirable, are generally assumed to be obligatory properties of this class of hypolipidemic drugs. In addition, the possibility has been raised that peroxisome proliferators as a class may be carcinogenic (17, 18). However, these latter effects are not observed under all conditions. In particular, clofibrate reduces serum lipid levels in both male and female rats, but did not affect peroxisome frequency or catalase activity in' females (9, 10). In comparative studies, clofibrate caused peroxisome proliferation in dogs and hamsters, but not in squirrel monkeys and guinea pigs, at the dose tested (9).5 This raises some doubt concerning our conclusion that the mechanism of action of hypotriglyceridemic drugs involves an effect on peroxisomes. There is considerable interest in finding new drugs capable of specifically and safely lowering serum lipid levels. In evaluating new compounds, it would be helpful to know as much as possible about the mechanism of action of the existing drugs. There are two separate systems for the p-oxidation ' To whom reprint requests should be addressed. * 2-(p-Chlorophenoxy)-2-methylpropionic acid ethyl ester. ' 2-Chloro-5-(3,5-dimethylpiperidinosulfonyl) benzoic acid. (4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio)acetic acid. Little information is available concerning the effect of hypolipidemic drugs on the abundance of peroxisomes in human liver. One patient treated with clofibrate had a lower mitochondria/peroxisomes ratio than three controls (15). This was interpretated as most likely being due to an increase in peroxisomes. Several female patients treated with Su-13437 did not show any notable change in the abundance of their hepatic peroxisomes (46). Journal of Lipid Research Volume 23, 1982 317 by gest, on N ovem er 6, 2017 w w w .j.org D ow nladed fom It is entirely possible, however, that the peroxisomal &oxidation enzymes could be induced without any effect on other peroxisomal enzymes or on the number of peroxisomes or on liver weight. Such induction would further support the proposed mechanism of action and would have important implications for the evaluation of new hypolipidemic drugs. In order to test this possibility, we have investigated the effect of clofibrate on female rats. In addition, we have tested the effects of bezafibrate,6 a clofibrate analog that is active at lower doses (19), and which has recently been introduced into clinical use in West Germany. A dose and protocol (25 mg/kg p.0. to male rats) was selected which has previously been shown to produce 63% of the maximal hypotriglyceridemic effect (19). In these two experiments, we found large elevations of the peroxisomal &oxidation system, with modest or sometimes no effects on other peroxisome parameters measured and on liver weight.