Why bile acid glucuronidation is a minor pathway for conjugation of endogenous bile acids in man
Authors: Alan F. Hofmann
Journal: Hepatology (2007)

Trottier et al.,1 in a masterful paper, show that human hepatic microsomes convert chenodeoxycholic acid predominantly to a C-24 ester glucuronide and that such glucuronidation is mediated mainly by the enzyme UGT1A3. Nonetheless, multiple studies have shown that in health as well as in liver disease, bile acid glucuronidation is a very minor pathway, based on measurements of urinary2, 3 and biliary bile acid glucuronides.2 The purpose of this note is to explain this apparent contradiction. In bile acid biosynthesis from cholesterol, the carboxyl group at C-24 remains in Coenzyme A linkage until the carboxyl group undergoes N-acyl amidation with glycine or taurine. Because the resulting bile acid amidates are relatively strong acids and fully ionized at intracellular pH, they cannot partition into the smooth endoplasmic reticulum and are not esterified with glucuronic acid, as shown by Trottier et al.1 The major flux of bile acids through hepatocytes consists of bile acids returning from the intestine. The majority of these is in conjugated form and thus cannot undergo glucuronidation. Some bile acids are also present in unconjugated form, formed by bacterial deconjugation in the distal intestine. Such unconjugated bile acids are transported across the sinusoidal membrane of the hepatocyte by FATP5 which immediately esterifies them with Coenzyme A.4 The Coenzyme A thio-ester rapidly transfers the bile acid to the amino group of glycine or taurine either in the cytosol and/or peroxisomes, again precluding glucuronidation. There are, however, at least four experimental situations, three in animals and two in humans, in which extensive glucuronidation of bile acids occurs. In the biliary fistula rat, when bile acids are infused at a rate exceeding the amidation capacity of the hepatocyte, glucuronidation occurs.5 In the perfused rat liver, when the hepatocyte is acidified by amiloride, glucuronidation of ursodeoxycholic acid (UDCA) increases markedly.6 Hyodeoxycholic acid (HDCA) (possessing α-hydroxy groups at C-3 and C-6) is a dihydroxy, secondary bile acid that occurs in pigs and rodents. When HDCA is given to healthy subjects. efficient ethereal hydroxylation at C-6 occurs and is mediated by UGT2B4 and UGT2B7,7, 8 presumably because this non-endogenous bile acid is a poor substrate for one or both of the steps involved in N-acyl amidation. The final instance of extensive bile acid glucuronidation occurs in both animals9 and humans10 when C23 (C-24 nor) dihydroxy bile acids are administered. Nor dihydroxy bile acids are poor substrates for the Coenzyme A ligase. The unconjugated bile acid partitions into the smooth endoplasmic reticulum and undergoes glucuronidation at C-3 or C-23 (animals) or only C-23 (humans), in agreement with the observations of Trottier et al.1 In humans, the C-6 glucuronide of hyodeoxycholic acid as well as the C-23 glucuronide of norUDCA are excreted in both urine and bile.7, 10 In summary, hepatic N-acyl amidation with glycine or taurine of newly synthesized bile acids as well as unconjugated bile acids returning from the intestine is highly efficient in health and in liver disease. As a result, ester glucuronidation at C-24, the major bile acid glucuronidation pathway in man, cannot occur because the two pathways are mutually exclusive. Thus, glucuronidation, the major phase II biotransformation pathway for many drugs, remains a very minor pathway for conjugation of endogenous bile acids in man. Alan F. Hofmann M.D.*, * Department of Medicine, University of California, San Diego, La Jolla, CA.