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Effects of clofibric and beclobric acid in rat and monkey hepatocyte primary culture: influence on peroxisomal and mitochondrial β-oxidation and the activity of catalase, glutathione S-transferase and glutathione peroxidase

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Abstract

The effect of hypolipidaemic compounds on peroxisomal fatty acid β-oxidation and on peroxisome morphology in the liver differs widely between rodent and primate species. We studied the relative importance of peroxisomal and mitochondrial β-oxidation of palmitate in primary cultures of hepatocytes isolated from rat and monkey liver in the absence or presence of clofibric acid or beclobric acid. It was demonstrated that it is possible to differentiate between peroxisomal and mitochondrial β-oxidation activities in intact cells. Overall β-oxidation of palmitate was ca. 30% higher in rat hepatocytes than in monkey liver cells. In both monkey and rat cell cultures the mitochondrial component was over 90% of the total palmitate β-oxidation. In rat hepatocyte culture clofibric acid and beclobric acid caused a 5- to 8-fold stimulation of peroxisomal β-oxidation, while in monkey cells this activity was not significantly increased. However, in cells derived from both species mitochondrial palmitate β-oxidation was increased (rat 2.5-fold; monkey 1.5-fold). These results indicate that the species differences in the increase in peroxisomal fatty acid oxidation are not a result of an inability to metabolize fatty acids in rat liver cell mitochondria. A comparison of the activity of enzymes involved in the detoxification of hydrogen peroxide showed that catalase and glutathione-S-transferase activity is 2.9-fold higher in monkey hepatocytes than in rat liver cells, while glutathione peroxidase activity was 1.6-fold higher in rat cells. When a comparison between both species is made for the ratio of hydrogen peroxide production over catalase activity, it can be concluded that this peroxide will have much smaller possibilities to escape from the peroxisomal compartment in monkey hepatocytes. These findings suggest that species differences in these enzyme activities can contribute to differences in susceptibility for peroxisome proliferator-induced carcinogenicity between rodents and primates.

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Authors and Affiliations

  1. Research Institute of Toxicology (RITOX), Utrecht University, PO Box 80.176, 3508 TD, Utrecht, The Netherlands

    W. C. Mennes, H. M. Wortelboer, G. A. M. Hassing, K. van Sandwijk & B. J. Blaauboer

  2. National Institute of Health and Environmental Protection (RIVM), PO Box 1, 3720 BA, Bilthoven, The Netherlands

    A. Timmerman

  3. Preclinical and Drug Safety Department, Zyma SA, CH-1260, Nyon, Switzerland

    B. P. Schmid

  4. Siegfried Pharma SA, CH-4800, Zofingen, Switzerland

    U. Jahn

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  1. W. C. Mennes
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  2. H. M. Wortelboer
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  3. G. A. M. Hassing
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  4. K. van Sandwijk
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  5. A. Timmerman
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  6. B. P. Schmid
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  7. U. Jahn
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  8. B. J. Blaauboer
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Mennes, W.C., Wortelboer, H.M., Hassing, G.A.M. et al. Effects of clofibric and beclobric acid in rat and monkey hepatocyte primary culture: influence on peroxisomal and mitochondrial β-oxidation and the activity of catalase, glutathione S-transferase and glutathione peroxidase. Arch Toxicol 68, 506–511 (1994). https://doi.org/10.1007/s002040050103

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  • DOI: https://doi.org/10.1007/s002040050103

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