THE EFFECT OF BILE SALTS AND SOME BILE-SALT ANALOGUES ON THE OXIDATION OF CHOLESTEROL BY LIVER MITOCHONDRIA

Abstract

The following new compounds were synthesized: taurohyodeoxycholic acid, tauro-3[beta]-hydroxyallocholanic acid, N-cholyl-[beta]-alanine, N-deoxycholyl-[beta]-alanine, N-cholylamino-methanesulfonic acid, N-deoxycholylaminomethanesulfonic acid, 4-methylpentanoyltaurine. The effect of these compounds and of taurine and glycine conjugates of natural bile (cholanic) acids on the oxidation of cholesterol, octanoate and propionate in vitro by isolated liver mitochondria was studied. Cholesterol oxidation by rat- and mouse-liver mitochondria was more sensitive to added bile salts than was oxidation by rabbit- and guinea-pig-liver mitochondria. Cholanic acid conjugates selectively inhibited cholesterol oxidation. The degree of inhibition increased as the number of oxygen functions on the steroid nucleus was decreased, but was independent of the configuration at C-5 (A/B ring junction) or the conjugated amino acid. Anionic detergents mimicked bile salts in selectively inhibiting cholesterol oxidation in vitro. The relative lipophilic character of these anionic detergents and of various taurocholanates was estimated by partition between water and a lipid solvent (chloroform) in the presence of methylene blue. The degree of mitochondrial swelling induced by inhibitors of cholesterol oxidation was measured optically. The findings are discussed in relation to proposals that cholesterol oxidation to bile salts in vivo is subject to negative-feedback control.