Comparison of clofibrate and ethyl-5-(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate induced changes in serum lipoprotein cholesterol and hepatic peroxisome proliferation in the normal rat.

Clofibrate and ethyl-5(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate (HMP), at 0.1 and 0.25% in the diet, were evaluated in normal rats. Effects on serum lipoprotein cholesterol, liver cholesterol and peroxisome proliferation changes were compared. Both doses of HMP significantly lowered high density lipoprotein cholesterol (HDL-C) and total cholesterol (mean 22% and 18%). The distribution of cholesterol in the lipoproteins was altered (p less than 0.05) and liver weights were increased 18% by the 0.25 dose of HMP. Clofibrate treatment increased (p less than 0.01) the combination of very low and low density lipoprotein cholesterol (VLDL + LDL-C) by 42% at the 0.1% dose and lowered HDL-C by 28% at the 0.25% dose; total-C was not changed from control values. Both levels of clofibrate shifted the distribution of lipoprotein cholesterol, increased liver weights (mean 69%) and reduced liver cholesterol (mean 33%). Image analysis of peroxisome changes showed that both doses of HMP and clofibrate increased peroxisome numbers (mean 71% vs 218%), with activity of HMP significantly lower than clofibrate. Measurement of carnitine acetyltransferase (CAT) activity (nmCoASH released/mg protein/minute) showed no significant increases in liver samples from HMP-treated rats, while clofibrate induced large increases in CAT activity, which were significant compared to control and HMP values. While having chemical structural similarity to clofibrate, HMP appears to cause comparable hypocholesterolemic activity without comparable levels of hepatomegaly and peroxisome proliferation.

Corneal lesions induced by antidepressants: a selective effect upon young Fischer 344 rats.

Within a few days of dosing with various structurally unrelated antidepressants, young Fischer 344 rats display punctate lesions on the posterior surface of the cornea. Similar lesions are not seen after treatment with stimulants, an anticholinergic, a serotonin uptake blocker or an alpha adrenergic antagonist. These lesions are peculiar to the Fischer strain; four other strains displayed no such effects. Within the Fischer strain, sensitivity to the lesion-inducing effects of antidepressants is progressively lost with increasing age and adults are insensitive. Examination of the corneal lesions with transmission and scanning electron microscopy revealed that the lesion involved focal eruptions of the endothelium containing fibroblasts, necrotic cells, collagen and mineralized deposits. The latter were confirmed by energy-dispersive X-ray analysis to contain calcium. Thus the reported corneal lesions are unusual in their morphology as well as in their strain, age and drug specificity.

Renal amyloidosis in KK mice that may be misinterpreted as diabetic glomerulosclerosis.

A normoglycemic, normoinsulinemic, "lean" phenotype KK mouse having a morphologically normal pancreatic islet had renal lesions reminiscent of diabetic glomerulosclerosis described in the literature for KK mice. Most of these animals also had splenomegaly. Using histochemical and ultrastructural methods, the renal and splenic lesions were demonstrated to be amyloidotic. Extensive deposits of amyloid were found in the liver and adrenals. Amyloidosis was found in all lean KK mice 4 months of age or older and in five of 11 C57BL/6J mice over 1 year of age. The validity of data attributing glomerulosclerosis to diabetes in mice that are neither glucosuric nor hyperglycemic or that show normal tolerance to glucose load should be questioned until amyloidosis is ruled out.