Enhancement of cholesterol turnover in rats by a catatoxic steroid (PCN) and a bile acid sequestrant (colestipol-HCl)

Abstract

Catatoxic steroids induce hepatic microsomal enzymes. To determine if cholesterol catabolism to bile acids by microsomal enzymes is stimulated by a catatoxic steroid, effects of pregnenolone-16α-carbonitrile (PCN) alone or with colestipol-HCl on cholesterol 7α-hydroxylase, cholesterol synthesis and cholesterol turnover were studied. Male rats fed diets containing colestipol (1%), PCN (0.085%), colestipol plus PCN, or basic diet were injected with [1,2,-³H]-cholesterol complexed with serum lipoproteins. Serum cholesterol specific radioactivity was measured for 49 days. Hepatic cholesterol and bile acid synthesis were estimated by [1-¹⁴C]-acetate incorporation and cholesterol 7α-hydroxylase activity. Turnover curves were analyzed using a three-pool model. PCN significantly increased all rate constants and cholesterol production rate (10.75 to 12.87 mg/day), which in this model is a measure of total body cholesterol turnover. Colestipol significantly increased total body cholesterol turnover (10.75 to 19.91 mg/day) and the excretion rate constant (0.44 to 0.88 day⁻¹) and increased acetate incorporation 6-fold and cholesterol 7α-hydroxylase activity 2-fold. PCN only slightly inhibited the latter. Effects of colestipol plus PCN were not different from those of colestipol alone. No treatment significantly changed cholesterol serum levels overall. Colestipol results are consistent with reported data for bile acid sequestrants. PCN markedly increased cholesterol flux between pools; it does not appear to induce and may, in fact, inhibit bile acid synthesis, perhaps by decreasing availability of necessary cofactors or cholesterol substrate.