Effects of propionic acid and pravastatin on HMG-CoA reductase activity in relation to forestomach lesions in the rat.

Abstract

Administration of 4% propionic acid in powdered diet to rats for 12 weeks induces severe hyperplastic lesions in the forestomach mucosa. The mechanisms underlying this damage are not yet clear. Several lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors such as lovastatin and simvastatin produce forestomach lesions similar to propionic acid after oral administration and the degree of alterations is correlated with their in vitro inhibitory potency (Kloss et al. 1991). Therefore it is possible, that sustained inhibition of HMG-CoA reductase and induction of hyperplasias may be somehow connected. For that reason we investigated, whether or not propionic acid has any influence on HMG-CoA reductase activity in vitro and in vivo, because propionic acid has been suggested to suppress liver cholesterol synthesis, and also whether or not pravastatin, a more polar HMG-CoA reductase inhibitor than lovastatin displays similar effects on forestomach mucosa. In untreated forestomach microsomes in vitro, propionic acid at a concentration of 51 mM (pH 5.7) inhibited HMG-CoA reductase activity by 51 + or - 10%, but at pH 7.2 no inhibition of the enzyme could be detected. Furthermore 4% propionic acid-treatment did not lower serum cholesterol. In contrast to lovastatin (Kloss et al. 1991), oral administration of pravastatin (up to 25% in the diet) did not produce any forestomach lesions in the rat. On the other hand, pretreatment with pravastatin revealed that HMG-CoA reductase activity in microsomes exceeded the activity of control forestomach and liver microsomes by 4.9 fold and 6.7 fold respectively, whereas no induction of this enzyme (neither liver nor forestomach) could be observed by pretreatment with 4% propionic acid for 12 weeks. Despite increased hepatic HMG-CoA reductase activity, pravastatin-treatment significantly lowered serum cholesterol levels of rats. These results show that sustained inhibition of HMG-CoA reductase activity in forestomach microsomes is not strongly connected with hyperplasia development.