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Evidence for the existence in rat and rabbit liver of two microsomal epoxide hydrolases with radically different substrate specificities was obtained, one with a broad specificity (EHb), whilst the other catalyzed the hydrolysis of cholesterol 5 alpha,6 alpha-oxide (EHch), a reaction taken as diagnostic since it was not observed with pure fractions of EHb. The two enzymes were physically separated by immunoprecipitation using antibodies which had been raised against EHb purified to apparent homogeneity. The substrate specificity of the two enzymes is radically different and mutually complementary. Cholesterol 5 alpha,6 alpha-oxide has a trisubstituted oxirane ring. All epoxides of this nature tested to date were not, or very poor, substrates of EHb. The two enzymes can also effectively be discriminated by inhibitors, in that 5 alpha,6 alpha-imino-5 alpha-cholestane-3 beta-ol potently inhibits EHch but not EHb whilst 1,1,1-trichloropropene oxide has the opposite specificity. The cytosolic EH did not significantly contribute to the catalysis of the hydrolysis of cholesterol 5 alpha,6 alpha-oxide.

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A number of structurally unrelated hypolipidaemic agents and certain phthalate-ester plasticizers induce hepatomegaly and proliferation of peroxisomes in rodent liver, but there is relatively limited data regarding the specific effects of these drugs on liver non-parenchymal cells. In the present study, liver parenchymal, Kupffer and endothelial cells from untreated and fenofibrate-fed rats were isolated and the activities of two enzymes associated with peroxisomes (catalase and the peroxisomal fatty acid P-oxidation system) as well as cytosolic and microsomal epoxide hydrolase were measured.Microsomal epoxide hydrolase, cytosolic epoxide hydrolase and catalase activities were 7 -12-fold higher in parenchymal cells than in Kupffer or endothelial cells from untreated rats; the peroxisomal fatty acid f3-oxidation activity was only detected in parenchymal cells. Fenofibrate increased catalase, cytosolic epoxide hydrolase and peroxisomal fatty acid P-oxidation activities in parenchymal cells by about 1.5, 3.5-and 20-fold, respectively. The induction of catalase (2 -3-fold) and cytosolic epoxide hydrolase (3 -5-fold) was also observed in Kupffer and endothelial cells ; furthermore, a low peroxisomal fatty acid P-oxidation activity was detected in endothelial cells. Morphological examination by electron microscopy showed that peroxisomes were confined to liver parenchymal cells in untreated animals, but could also be observed in endothelial cells after administration of fenofibrate.Peroxisomes are ubiquitous cytoplasmic organelles present in plant and animal cells. They have both catabolic and anabolic functions [ 11 ; the former include respiration and the P-oxidation of fatty acids [2, 31. Respiration is catalyzed by oxidases which form H 2 0 2 and catalase which decomposes it. The peroxisomal P-oxidation reactions are the same as those of mitochondria1 f3-oxidatioq with the exception of the first reaction, in which electrons are transferred to oxygen by an oxidase in the peroxisomes, instead of to the electron transport chain, as in mitochondria.A small quantity of peroxisomes is observed in mammalian liver parenchymal cells [4]. After administration of several structurally unrelated hypolipidaemic drugs, or certain phthalate-ester plasticizers, a marked hepatomegaly and a large increase in both number and size of peroxisomes in liver parenchymal cells occurs [5]; furthermore, the activities of several enzymes in the liver (e.g. catalase, peroxisomal fatty acid P-oxidation system, epoxide hydrolase) are enhanced The mammalian liver is composed of several different cell types. Parenchymal cells constitute about 90% of the total cell mass, but only represent 65% of the total cell number [8]; the remainder corresponds to non-parenchymal cells, mainly Kupffer and endothelial cells. There is limited data regarding the specific effects of peroxisome proliferators on liver non-