Meconium bile acids

In 1971, Makino et al. found that considerable amounts of 3jS-hydroxychol-5-en-24-oic acid were excreted in urine of children with extrahepatic biliary atresia [111]. Since then, the unsaturated C24 bile acid has been identified in human meconium [112,113], amniotic fluid [114,115], gallbladder bile from premature and term infants [116], urine from children and adults, both healthy and with liver disease [82,117], and bile and feces from newborn and fetal guinea pigs [118]. The natural occurrence of 3j8-hydroxychol-5-en-24-oic acid suggests that the side chain of cholesterol is degraded before modification of the steroid ring system (Chapter 9). 

Dihydroxychol-5-en-24-oic acid has been found as a minor bile acid in human meconium [113] and urine [82], and 7a,12a-dihydroxy-3-oxochol-4-en-24-oic acid in gastric contents from neonates with high intestinal obstruction [110]. 

Although cholesterol is the major source of 5)9-bile acids, an unsaturated acid, 3)8-hydroxy-5-cholenic acid [174] has been found in meconium, mainly as the sulfate [175], in bile of a boy with a deficiency of 3)8-hydroxysteroid dehydrogenase [176], and in urine of healthy persons and individuals with liver disease [164]. The details of metabolism of 3)8-hydroxy-5-cholenic acid to lithocholate have not been entirely elucidated, but the mechanism for conversion of the 3/8-hydroxy-A to the 3-oxo-A derivative has been formulated in the C27 series (cf. Chapter 9). Briefly, the 3)8-ol is dehydrogenated by a microsomal enzyme fortified with NAD to provide the 3-oxo-A system [177,178]. Whether a A - A" isomerase is essential is not known, since there is no direct evidence for the formation of the intermediary 3-oxo-A system the rate-limiting step is the dehydrogenation of the 3)8-ol which may prevent accumulation of the 3-oxo-A system [177]. The reduction of the double bond at 4-5 to the 5)8- or 5a-bile acid is catalyzed by the respective A -3-oxosteroid 5)8- or 5 -reductase obtained from liver cytosol [170], and has been purified about 10-fold [178]. The formation of the 3-oxo-5/9 derivative requires the enzyme and NADPH the proton from the A side (4A-NADPH) appeared in the product as the 5)8-H, whereas the proton at C-4 is derived from the aqueous medium. Formation of the 5a derivative requires (4B-NADPH) in a similar mechanism (Fig. 4) [179], Reduction of the 3-0X0 product is then catalyzed by 3a-hydroxysteroid dehydrogenase as discussed above. 

Bile acids identified from (A) human urine, or (B) human meconium... 

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 newly born infant gut contents include a complex mixture of neutral and acidic steroids generally present as glycine and taurine conjugates or as sulphates[4]. The pattern of bile acids in meconium probably represents the accumulation of maternal and foetal products and is dominated by cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid and hyocholic acid[5]. Epimeric, unsaturated or side-chain shortened bile acids have also been detected in meconium[6]. This bile acid profile is rapidly lost in infants and, at 18 months, the principle bile acids excreted are cholic acid and... 

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