Bile acid conjugates animals

Bile acid conjugation with a xenobiotic acid Is a recently discovered metabolic pathway ( 8 ). An anlllno acid from the pyrethrold Insecticide fluvallnate acylates the 3-posltlon of natural bile acids In rats ( 85), chickens (86). and a cow (.87), and these conjugates represent 5-12X of the C-resldue In feces (Figure 14). Eight different bile acids have been shown to conjugate with this anlllno acid In these animal species, but so far no other xenobiotic acids have been reported to follow a similar pathway. 

The intestinal microflora of man and animals can biotransform bile acids into a number of different metabolites. Normal human feces may contain more than 20 different bile acids which have been formed from the primary bile acids, cholic acid and chenodeoxycholic acid [1-5], Known microbial biotransformations of these bile acids include the hydrolysis of bile acid conjugates yielding free bile acids, oxidation of hydroxyl groups at C-3, C-6, C-7 and C-12 and reduction of oxo groups to give epimeric hydroxy bile acids. In addition, certain members of the intestinal microflora la- and 7j8-dehydroxylate primary bile acids yielding deoxycholic acid and lithocholic acid (Fig. 1). Moreover, 3-sulfated bile acids are converted into a variety of different metabolites by the intestinal microflora [6,7]. 

The hydrolysis of bile acid conjugates is probably the initial reaction catalyzed by intestinal bacteria. Therefore, primarily free bile acids are isolated from the feces of man and animals [1-5]. The bulk of the free bile acids in feces of man is deoxycholic acid and lithocholic acid which are generated by the 7 -dehydroxylation of cholic acid and chenodeoxycholic acid, respectively. A portion of fecal acids is absorbed from the intestinal tract, returned to the liver where they are conjugated and again secreted via biliary bile. Therefore, the final composition of biliary bile acids is the result of a complex interaction between liver enzymes and enzymes in intestinal bacteria. 

In addition to changing the physical properties of bile acids, conjugation also alters their physiological properties. On the basis of extremely limited evidence, it seems likely that the bile acid pool of animals with exclusively taurine conjugates is maintained chiefly by active absorption from the ileum. 

It is probable that most data which have been collected on cell metabolism with the use of laboratory animals are applicable to the healthy human being. During conditions of disease, however, this may not always be true since many diseases cannot be identically reproduced in animals, e.g., irtfectious hepatitis. Furthermore, species differences are very pronounced, especially in bile acid conjugation (Ilaslewood, 1967). 

Nearly all bile acids are choleretic agents that is, they increase bile flow when infused intravenously into various animal species. In all vertebrtae species examined, there is a close relationship between bile flow and the hepatic excretion rate of bile acids (B24). Acute interruption of the enterohepatic circulation of bile acids in man by diversion of bile flow causes the rate of bile secretion to decrease by about 50% (TIO). Thus, the excretion of bile acids from the liver is the major determinant of bile water and solute excretion, predominantly because of the osmotic activity of bile acids in bile. Some interesting studies in dogs have been performed with the bile salt taurodehydrocholate (taurine conjugate of 3,7,12-triketo-5fl-cholan-24-oic acid), which, for stereochemical reasons, cannot form micelles and should therefore have greater osmotic activity than other bile acids. At the same... 

Lithocholic acid and its conjugates are bile acids which are not choleretic, but have the opposite effect in causing intrahepatic cholestasis in experimental animals (F5, Jl, 02), and presumably man. The cholestatic effect of these bile acids is abolished if cholic acid is administered simultaneously, probably because of the ability of cholic acid to solubilize lithocholic acid in micelles (K2, L5). To explain the pathogenesis of lithocholate-induced cholestasis, it has been suggested that lithocholate binds to the bile canalicular membrane, increases its cholesterol content and reduces its permeabflity to water and ions (Kl, K2). 

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]. 

The efficient intestinal absorption of bile acids involves both active and passive absorption, but little information on the relative sites and mechanisms of absorption and on their contribution to the entire enterohepatic cycle of bile acids exists. Although the contribution of passive and active absorption of bile acids in the rat small intestine has been measured (20), no data are available for other species. The major site of absorption in all vertebrates appears to be the ileum, where an active transport site exists (14,15). Free bile acids are absorbed passively in the jejunum by nonionic diffusion, dihydroxy acids being absorbed more rapidly than trihydroxy acids (21,22). Perfusion studies in the human jejunum have suggested that glycine dihydroxy bile acids may be absorbed to some extent, and additional evidence for jejunal absorption of bile acids has been obtained in patients and animals with ileal resection (97,98). No information exists on the importance of jejunal bile acid absorption in health in man. Taurine-conjugated bile acids do not appear to be absorbed in the human jejunum (24). 

In humans as in animals the primary bile acids are converted in various ways, and more than 25 different secondary bile acids have been identified in human feces. Deoxycholate and lithocholate stand out because they are found in large quantities. These secondary bile acids are derived from cholate and chenodeoxycholate through 7-dehydroxylation by enzymes of colonic bacteria. In man, primary and secondary bile salts are all conjugated to two amino acids, taurine and glycine, and thus the amounts of free bile salts are very small. Conjugated bile salts... 

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