Fibrates are widely prescribed in hyperlpidemic patients to prevent
atherosclerosis. Their
therapeutic use, however, can be associated with adverse effects like
gastrointestinal disorders,
myalgia,
myositis and hepatotoxicity. In rodents large doses can even cause
hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the
cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily
oral administration of 2 mg/kg
body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg
body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized
glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum
lipid concentrations, after
fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in
glycogen content, but no signs of
inflammation. After
fibrate administration histologically a
hypertrophy, an
eosinophilia, a reduced
glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher
CYP1A1 andCYP2E1 expression, but lower immunostaining for
CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to
fibrate treatment especially
CYP2E1 and CYP4A1, but also
CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated
monooxygenase activities were also elevated in most cases. In general, effects of
clofibric acid and
clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of
ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent
fibrates and their
glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over
ciprofibrate or
clofibric acid.