ROLE OF BILE-SALT HYDROPHOBICITY IN HEPATIC MICROTUBULE-DEPENDENT BILE-SALT SECRETION

Under basal conditions, bile sail secretion by the liver is not affect ed by microtubule disruption. However, when a bile salt load is impose d on the liver, a microtubule-dependent secretion mechanism is recruit ed (J. Lipid Res. 1988. 29: 144-156). We tested the hypothesis that re cruitment of this microtubule-dependent mechanism is influenced by the relative hydrophobicity of the bile salts being secreted. Intact male rats were depleted of bile salts by overnight biliary diversion, pret reated with colchicine (a microtubule inhibitor) or its inactive isome r, lumicolchicine (control), and reinfused intravenously with bile sal ts of increasing hydrophobicity (taurodehydrocholate < tauroursodeoxyc holate < taurocholate) at 200 nmol/min.100 g. After 45 min, when stead y-state bile salt secretion was achieved, tracer [H-3]taurocholate was administered intravenously. The colchicine-insensitive component of b ulk bile salt secretion was constant at similar to 130 nmol/min.100 g, and the colchicine-sensitive component increased from similar to 0 to 35 and 60 nmol/min.100 g, respectively, with reinfusion of the more h ydrophobic bile salts. Retained bile salts accumulated in the liver an d serum and were detectable in urine. Peak biliary secretion of [H-3]t aurocholate in control animals increased linearly from 15.3 to 18.0% a dministered dose/min with increasing hydrophobicity of the secreted bi le salts (P < 0.002). In colchicine-pretreated animals, peak secretion rates decreased linearly from 13.8 to 9.2%/min (P < 0.001), with maxi mal inhibition in taurocholate-reinfused animals (P < 0.01). Utilizati on of a microtubule-dependent secretion mechanism increases with incre asing bile salt hydrophobicity. This mechanism permits more efficient hepatic secretion of bile salts, but increases the susceptibility of b ile salt secretion to microtubule disruption. We postulate that microt ubule-dependent insertion of bile salt transporters into the canalicul ar membrane underlies the enhanced bile sale secretion observed when a bile salt load is imposed upon the liver.