The effect of beclobric acid and clofibric acid on peroxisomal beta-oxidation and peroxisome proliferation in primary cultures of rat, monkey and human hepatocytes.
The peroxisome-proliferating effects of clofibric acid and beclobric acid were studied in primary cultures of hepatocytes derived from rat, monkey (Macaca fascicularis) and human liver. Determination of peroxisomal fatty acid beta-oxidation and morphometrical analysis of the peroxisomal compartment were performed after incubation of 1-day-old hepatocyte cultures for 3 days with either compound. In rat liver cell cultures both compounds gave a 10-fold increase in peroxisomal beta-oxidation, a 3-fold increase in the relative number of peroxisomes and a 1.5-fold increase in the mean size of peroxisomes. Beclobric acid gave its maximal effect at a concentration of 10 microM, which is at least one order of magnitude lower than the maximum-effect concentration of clofibric acid. At concentrations greater than 300 microM beclobric acid was cytotoxic. No stimulation of peroxisomal fatty acid beta-oxidation was found in either monkey or human hepatocyte cultures. Morphometrical analysis also showed no increase in the peroxisomal compartment in cultures derived from these species, as indicated by the lack of increase in both relative number and size of peroxisomes. In all three species tested beclobric acid was equally cytotoxic for hepatocytes in vitro. These results are of relevance for the interpretation of the peroxisome-proliferating effects of clofibrate and similar compounds in rats. Since peroxisome proliferation may be correlated to increased hepatic tumour incidences in the rat, the absence of peroxisome proliferation in primates suggests the absence of tumourogenic activity by hypolipidemic compounds in these species.
Blaauboer
B J
BJ
Research Institute of Toxicology, University of Utrecht, The Netherlands.
van Holsteijn
C W
CW
Bleumink
R
R
Mennes
W C
WC
van Pelt
F N
FN
Yap
S H
SH
van Pelt
J F
JF
van Iersel
A A
AA
Timmerman
A
A
Schmid
B P
BP
D000328:Adult; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000648:ultrastructure*; D008252:Macaca fascicularis; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D001559:Benzhydryl Compounds; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D002994:Clofibrate; C020978:beclobrate