Lipid-regulating agents and the mammalian hepatic peroxisome proliferative response.

Abstract

Certain lipid-regulating agents induce hepatomegaly, hepatic peroxisome proliferation and hepatocarcinoma in rodents. Evaluation of this response is necessary to appreciate its relevance to man. In these investigations, the rodent hepatic peroxisome compartment was quantified following administration of lipid-regulating agents, acetylsalicylic acid (ASA) or dibutylphthalate (DBP). Data were used to relate chemical structure, peroxisome proliferation and lipid-regulation. Also addressed was peroxisome biogenesis and differing characteristics of these subcellular phenomena. These studies identified compounds and their substituents, responsible for peroxisome proliferation. Aryloxyalkanoic acids and amides, as well as thio, benzimidazole, phenylpiperazine, oxazole and adamantyloxy derivatives induced varying degrees of proliferation. Proliferation with amides was not generally as extensive as seen with aryloxyalkanoic acids (clofibrate, gemfibrozil and bezafibrate). Substitution of the dimethyl ester component eliminated peroxisome proliferation. Evidence is reported here of a significant correlation between peroxisome proliferation and circulating high-density lipoproteins (HDL). Partition coefficients and molecular weights also were associated with HDL-elevation. Therefore, chemical structure, peroxisome proliferation and lipoprotein metabolism were associated. Quantitative evaluation of peroxisome biogenesis confirmed differing characteristics depending on chemical structure, treatment duration, species, strain and sex. The immediacy, magnitude and reversibility of the proliferative response was illustrated following administration of biphenylylmethylvaleric acid. The timing and degree of this proliferative response differed in the centrilobular and periportal hepatic regions. A reversible shift from peroxisomes with paracrystalline cores to non-nucleated organelles was demonstrated. A minimal though variable response in hamsters establishes variable strain susceptibilities, and suggests the hamster may be a more appropriate rodent model for human risk assessment. Characteristics of peroxisome biogenesis, distinct from those noted with lipid-regulating agents, were evident following DBP or ASA administration. Investigations of hepatic peroxisome responses establish characteristics of peroxisome proliferation, distinguishing adaptive responses from hepatotoxicity and perhaps neoplastic transformation.