CIPROFIBRATE-RACEMATE AND ENANTIOMERS - EFFECTS OF A 4-WEEK TREATMENTON MALE INBRED FISCHER RATS - A BIOCHEMICAL AND MORPHOLOGICAL-STUDY

Ciprofibrates (racemate and both enantiomers, Raccip, R- and Scip) wer e administered orally in doses of 1 and 10 mg/kg once daily over 28 da ys to male inbred Fischer 344 rats, age 90-110 days at the beginning o f the experiment. Body mass gain was observed in all groups. The 1 mg groups showed almost no difference to the control group. The 10 mg gro ups exhibited less body mass gain, most pronounced in the Scip group. Liver masses were increased in a dose dependent manner up to more than 200%, only the 10 mg Scip group was not significantly different from the 1 mg group which exhibited an increase in liver weight to about 17 5%. Also the kidney weights increased to 130%, whereas thymus and sple en weights were decreased in the high dose groups. Liver microsomal cy tochromes P450 (P450) concentrations were not altered in the 1 mg grou ps and distinctly lowered in the 10 mg groups. Ethoxyresorufin and eth oxycoumarin O-deethylations were lowered in all experimental groups in a dose dependent manner, after administration of the high doses down to 30% of the control levels or less. Pentoxyresorufin O-depentylation , however, was increased in all 1 mg groups. In the high dose groups i t was not altered. Ethylmorphine N-demethylation was decreased after a dministration of the high doses by about 50%, but only Scip decreased this reaction also after administration of the low dose. NADPH/Fe2+-st imulaled microsomal luminol and lucigenin amplified chemiluminescence was increased, whereas hydrogen peroxide formation was depressed even by the low doses to 50% of the normal values, to about 25% by the high doses. Microsomal lipid peroxidation, however, was only slightly or n ot influenced. Glutathion concentrations (in the reduced and the oxidi zed form) were increased in a dose dependent manner by about 20 to 30% , the concentration of lipid peroxides was not significantly influence d. Thus, the effects of the enantiomers were not different and were si milar to those of the racemate. In serum, cholesterol and triglyceride s were only moderately lowered. Albumin concentrations were significan tly enhanced in all groups, total proteins after 1 mg/kg Raccip only. Serum bilirubins were not altered, and among the indicator enzymes for liver damage only ALAT, alkaline phosphatase and the dehydrogenases w ere increased, in no case higher than twofold. Histologically distinct effects were seen after administration of both doses, more pronounced after 10 mg/kg, but with no differences between the enantiomers and R accip: marked hypertrophy of the hepatocytes, reduced staining of the nuclei, strongly acidophilic granulated cytoplama, no basophilia of th e cell bodies, loss of glycogen. These changes were most pronounced ar ound the central veins. Hepatocyte apoptoses also were observed. By im munohistochemistry an increased staining was seen for all P450 isoform s tested (1A1, 2B1, 2E1, 3A2 and 4A1), predominantly perivenously and most pronounced after administration of the high doses without differe nces between Rcip, Scip or Raccip (preliminary results). By electron m icroscopy a moderate proliferation of per oxisomes after treatment wit h 1 mg/kg Cips with a ratio between mitochondria and peroxisomes of ab out 1:1 (controls: 10:1) was observed, and the peroxisomes were a more heterogeneous population. The relative portions of glycogen and both forms of the ER decreased. Treatment with 10 mg/kg Rcip, Scip or Racci p led to a strong increase in the number of peroxisomes, in some hepat ocytes the ratio between mitochondria and peroxisomes was 1:3 with an increased heterogeneity among the peroxisomes evidenced by a broad ran ge of electron densities. Most peroxisomes lacked a nucleoid. Thus, th e biochemical effects differed only slighly and the morphological effe cts of the enantiomers were not different and were similar to those of the racemate.