Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348.

Abstract

The changes occurring in hepatocytes of F-344 male rats during a 3-wk treatment with a hypolipidemic agent, 1-methyl-4-piperidyl-b/s[p-chlorophenoxy]acetate (Sail 42-348), have been evaluated by morphometric and biochemical methods. The twofold increase in liver weight resulted from a significant increase in hepatocyte cytoplasm as well as a moderate increase in the number of liver cells. The peroxisome population and SER played an overwhelming part in the hypertrophy of hepatocytic cytoplasm. The relative volume and the surface density of peroxisomes increased ninefold and sevenfold, respectively. The increase in the collective peroxisome volume resulted from an increase in both the number and the average volume of peroxisomes. The SER also demonstrated a substantial increase in these values. The relative volume and surface density of mitochondria were not significantly altered in comparison to controls, while these values for RER decreased onefold. Studies on the lobular distribution of cytoplasmic organeUes before and during treatment revealed that the relative volume and surface density of peroxisomes and SER increased from periportal to centrilobular cells of the hepatic lobule, whereas mitochondrial values decreased from periportal to centrilobular cells. The RER values were fairly constant in different parts of the hepatic lobule. The increase in peroxisome and SER volume and surface area was first evident within the first 3 days of Sail 42-348 treatment and these values continued to increase, reaching a steady state within 2 wk. The time course of increase in catalase and carnitine acetyltransferase activities correlated with the morphometric data on the peroxisomes. After cessation of Sail 42-348 treatment, the peroxisome values decreased rapidly within the first 3 days and reached control levels within 1 wk. Moderate reduction in SER values occurred after withdrawal of the drug, but these values remained higher than controls even after 2 wk, suggesting that the reduction in the amount of circulating peroxisome proteins may result in empty SER channels. On the 4th day of drug withdrawal a significant increase in the relative volume and surface density of lysosomes was

Fine Structural Changes in the Hepatic Microbodies of Rats Treated With Hypolipidemic Agents, Gemfibrozil and Clofibrate

“…Proliferation of microbodies due to the effect of several hypolipidemic agents has been examined by biochemical assay of catalase (7), by electron microscopic cytochemistry (24) and more recently by morphometric analysis (18,29).…”

Nonradioactive in situ hybridization for detection of mRNAs encoding for peroxisomal proteins: heterogeneous hepatic lobular distribution after treatment with a single dose of bezafibrate.

“…Bout et al (1990) also reported that transcripts for 3-oxoacyl-CoA thiolase, another enzyme of the lipid 0-oxidation pathway, were increased in centrilobular hepatocytes. Because the proliferation of peroxisomes as determined by morphometry (Moody and Reddy, 1976) and the concentration of PH protein as revealed by quantitative immunogold labeling are also more pronounced in the same region of the liver lobule (Lindauer et al, 1994), it is likely that pericentral hepatocytes respond more vigorously to peroxisome-proliferating agents. Recently, several nuclear receptors, called peroxisome proliferator-activated receptors (PPARs), have been identified and were shown in transactivation assays to induce the transcription of peroxisomal &oxidation enzyme genes (Wahli et al, 1995;Green and Wahli, 1994).…”

“…Whereas the increased transcription of genes encoding the p-oxidation enzymes has been well documented by Northern blotting (Nemali et al, 1988;Reddy et al, 1986), little is known about the exact spatial distribution of corresponding "As in the liver lobule. The proliferation of peroxisomes, however, is quite heterogeneous, with many compounds being more pronounced in pericentral (Zone 3) region of the liver lobule (Gorgas and Krisans, 1989;Baumgart et al, 1987;Moody and Reddy, 1976). Using immunoelectron microscopy with protein A-gold and quantitative image analysis, we recently showed that the elevation of individual P-oxidation enzymes varies in different parts of the liver lobule, depending on the type of xenobiotic compound used (Lindauer et al, 1994).…”

Peroxisome degradation in mammals

“…All the above effects of hypolipidemic drugs were fully reversed after withdrawal of the drugs. After cessation of the drugs, cellular peroxisome levels decreased to the control level within 1 week (9,27). To investigate the peroxisome degradation process, the decrease in proliferated peroxisomes was measured after withdrawal of the drugs.…”

“…Moody and Reddy reported that they administered the clofibrate derivative 1-methyl-4-piperidyl-bis[p-chlorophenoxy] acetate (SaH 42-348) to rats by mixing the reagent with chow at a concentration of 0.10% (wt/wt) for 3 weeks. By the treatment, the liver weight and the relative volume of peroxisomes increased 2-and 8.4-fold, respectively (9).…”