HEPATIC PEROXISOME PROLIFERATION IN RODENTS AND ITS SIGNIFICANCE FOR HUMANS

Peroxisomes are subcellular organelles found in all eukaryotic cells. In the liver they are usually round and measure about 0.5-1.0 mu m; in rodents they contain a prominent crystalloid core, but this may be ab sent in newly formed rodent peroxisomes as well as in human peroxisome s. A major role of the peroxisomes is the breakdown of long-chain fatt y acids, thereby complementing mitochondrial fatty-acid metabolism. Ma ny chemicals are known to increase the number of peroxisomes in rat an d mouse hepatocytes. This peroxisome proliferation is accompanied by r eplicative DNA synthesis and liver growth. No clear structure-activity relationships are apparent. Many of these peroxisome proliferators co ntain acid functions that can modulate fatty acid metabolism. Two mech anisms have been proposed for the induction of peroxisome proliferatio n. One is based on the existence of one or several specific cytosolic receptors that bind the peroxisome proliferator, facilitating its tran slocation to the cell nucleus and the activation of the expression of specific genes. The second, perhaps more general, hypothesis involves chemically mediated perturbation of lipid metabolism. These two hypoth eses are not mutually exclusive. Many peroxisome proliferators have be en shown to induce hepatocellular tumours, despite being uniformly non -genotoxic, when administered at high dose levels to rats and mice for long periods. Three mechanisms have been proposed to explain the indu ction of tumours. One is based on increased production of active oxyge n species due to imbalanced production of peroxisomal enzymes; it has been proposed that these reactive oxygen species cause indirect DNA da mage with subsequent tumour formation. In rodents, an alternative mech anism is the promotion of endogenous lesions by sustained DNA synthesi s and hyperplasia. Thirdly, it is conceivable that sustained growth st imulation may be sufficient for tumour formation. Marked species diffe rences are apparent in response to peroxisome proliferations. Rats and mice are extremely sensitive, and hamsters show an intermediate respo nse while guinea pigs, monkeys and humans appear to be relatively inse nsitive or non-responsive at dose levels that produce a marked respons e in rodents. These species differences may be reproduced in vitro usi ng primary culture hepatocytes isolated from a variety of species incl uding humans. The available experimental evidence suggests a strong as sociation and a probable casual link between peroxisome-proliferator-e licited liver growth and the subsequent development of liver tumours i n rats and mice. Since humans are insensitive or unresponsive, at ther apeutic dose levels, to peroxisome-proIiferator-induced hepatic effect s, it is reasonable to conclude that the encountered levels of exposur e to these non-genotoxic agents do not present a hepatocarcinogenic ha zard to humans. This conclusion is supported by the available, albeit limited, epidemiological data.