Cholate conjugates

Bile acids, which exist mainly as bile salts, are polar carboxylic acid derivatives of cholesterol that are important in the digestion of food, especially the solubilization of ingested fats. The Na and salts of glycocholic acid and tauro-cholic acid are the principal bile salts (Ligure 25.41). Glycocholate and tauro-cholate are conjugates of cholic acid with glycine and taurine, respectively. 

The first studies of specificity were carried out using cholate, the glycine and taurine conjugates and taurine conjugates of the dihydroxy bile acids cheno-deoxycholate and ursodeoxycholate. Kramer and colleagues prepared plasma membrane vesicles from rat liver and compared bile-acid transport with values from CHO cells stably expressing NTCP. This work established that transport by the liver enzyme was maximal when 2 hydroxyls were present,... 

The common bile salts in humans are glycine and taurine conjugates of sodium deoxycho-late (NaDOC) and sodium chenodeoxycholate (CDOC), dihydroxy bile salts, and sodium cholate (NaC, the trihydroxy bile salt). The ability of bile salts to increase transmucosal transport of solutes has been frequently stated [62,81,82]. Generally, the more hydrophobic dihydroxy bile salts act as more effective absorption enhancers in comparison to trihydroxy bile salts. For example, Gullikson et al. [83] have reported that the absorption of inulin, dextran, and albumin in the perfused rat jejunum was enhanced with dihydroxy but not with trihydroxy bile salts. 

In the duodenum s alkaline environment, bile acids become bile salts (e.g. sodium glyco-cholate). Bile acids are conjugated (joined together) with glycine or taurine, via formation of... 

FIGURE 2.7 Conjugation of glycine with cholate to form glycocholate. 

The formation of conjugates of taurine or glycine is induced by glucocorticoids, specifically dexamethasone [49]. In primary cultures of rat fetal liver dexamethasone increased and maintained taurine conjugation of cholate, chenodeoxycholate, and deoxycholate short-term cultures of adult rat hepatocytes maintained conjugation of bile acids with glycine and taurine [49]. Enzymatic activity was stimulated by low doses of ethynylestradiol [50], and has been verified in fetal liver [51]. 

Bile acids in meconium also reflect atypical synthesis. Back and Walter [209] reported on the presence of 14 bile acids obtained from meconium of 6 healthy infants (Table 2B). On the average 21% of chenodeoxycholate and of hyocholate and 8% of cholate were sulfated. Deoxycholate was the major bile acid of the sulfate fraction lithocholate, 3/8-hydroxy-5-cholenate [175] and 3, 12a-dihydroxy-5-cholenate were found only in the sulfate fraction, but quantities of lithocholate (range 0.3-1.4%) and 3i8,12a-dihydroxy-5-cholenate were small. The amount of l, 3tt,7a,12a-tetrahydroxy acid (79% as the taurine conjugate and 21% unconjugated) ranged from 3.6 to 11.1% of the total bile acids [209]. The feta bile adds of a number of animals, normal, adrenalectomized, thyroidectomized, or diabetic, are reviewed by Subbiah and Hassan ]210]. 

Zhu and Zhao prepared pH-sensitive polymeric vesicular aggregates using combshaped amphiphilic polymers, i.e., cholate grafted poly(L-lysine) (PLL-CA), with an amphiphilic PEG-doxorubicin (DOX) conjugate (Figure 2.11) [57c]. The pH sensitivity leads to better uptake of the vesicles by cancer cells (MCF-7) under conditions close to the extracellular environment of a solid tumour (pH = 6.5) and subsequent escape from endosomes after endocytosis. Moreover, if the pH value is lower the vesicles destabilise. 

---