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Hyodeoxycholic acid

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Hyodeoxycholic acid
Hyodeoxycholic acid
Names
IUPAC name
4-[(5R,8S,10R,13R,17R)-3,6-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
Other names
3α,6α-Dihydroxy-5β-cholan-24-oic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.001.349 Edit this at Wikidata
  • InChI=1S/C24H40O4/c1-14(4-7-22(27)28)17-5-6-18-16-13-21(26)20-12-15(25)8-10-24(20,3)19(16)9-11-23(17,18)2/h14-21,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15-,16+,17-,18+,19+,20+,21+,23-,24-/m1/s1 ☒N
    Key: DGABKXLVXPYZII-SIBKNCMHSA-N ☒N
  • InChI=1/C24H40O4/c1-14(4-7-22(27)28)17-5-6-18-16-13-21(26)20-12-15(25)8-10-24(20,3)19(16)9-11-23(17,18)2/h14-21,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15-,16+,17-,18+,19+,20+,21+,23-,24-/m1/s1
    Key: DGABKXLVXPYZII-SIBKNCMHBP
  • O=C(O)CC[C@@H](C)[C@@H]4[C@]3(CC[C@H]1[C@@H](C[C@H](O)[C@@H]2C[C@H](O)CC[C@]12C)[C@@H]3CC4)C
Properties
C24H40O4
Molar mass 392.58 g/mol
Density ? g/cm3
Melting point 200 to 201 °C (392 to 394 °F; 473 to 474 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Hyodeoxycholic acid, also known as 3α,6α-Dihydroxy-5β-cholan-24-oic acid or HDCA, is a secondary bile acid, one of the metabolic byproducts of intestinal bacteria. It differs from deoxycholic acid in that the 6α-hydroxyl is in the 12 position in the former. The 6α-hydroxyl group makes HDCA a hydrophilic acid, a property it shares with hyocholic acid. HDCA is present in mammalian species in different proportions. It is the main acid constituent of hog bile, and for this reason it was used industrially as precursor for steroid synthesis before total synthesis became practical.

Metabolism

In rat intestinal microflora hyodeoxycholic acid is produced by a Gram-positive rod—termed HDCA-1—from several isomers of hyocholic acid and muricholic acid.[1] In pigs with a normal gastrointestinal flora the majority of hyodeoxycholic acid found in bile is of secondary nature, but a small amount was also found in germ free pigs, which supports the hypothesis that HDCA may be a primary bile acid in this species.[2] In healthy humans only traces of HDCA have been found in urine, but in patients with cholestatic liver disease or intestinal malabsorption a significant amount has been found excreted.[3]

Hyodeoxycholic acid undergoes glucuronidation in human liver and kidneys.[4][5] Glucuronidation of hyodeoxycholic and hyocholic acids was observed to occur extensively at the 6α-hydroxyl group, unlike primary bile acids which form 3α-hydroxy-linked glucuronides. This suggests an important pathway for the elimination of toxic and cholestatic bile acids, e.g. lithocholic and chenodeoxycholic acids which can form hyodeoxycholic and hyocholic acids, respectively, after 6α-hydroxilation.[6] The enzyme family responsible for glucosidation of hyodeoxycholic acid in human liver is UDP-glucuronosyltransferase. Both the UGT2B4 and UGT2B7 isoforms are able to glucuronidate HDCA.[7][8] This is an example of redundancy in protection against harmful endogenous compounds provided by UGT isoforms, which present distinct but frequently overlapping substrate specificity. A common amino-acid residue that confers these two isoforms specificity to HDCA has been identified in 2006.[9]

Animal model studies support the concept that bile acids may play a role in the development of colon cancer. Deoxycholic acid (DCA) is believed to be tumor promoter, while ursodeoxycholic acid (UDCA) was found to suppress the development of colon tumors. The mechanism that accounts for this difference in function is not clear. In vitro studies found that DCA induces apoptosis in some colon cancer cell lines, while UDCA arrests cell proliferation without inducing apoptosis. In these studies HDCA exhibited biological activity that is intermediate to DCA and UDCA, arresting growth for a time, but causing apoptosis after extended exposure.[10][11]

Applications

It was known since 1939 that HDCA could be used to synthesize progesterone.[12] A decade later, an analysis of the composition of hog bile determined that HDCA accounted for approximately 40% of its acid contents.[13] In the 1950s, lacking access to vegetal precursors of steroids, like diosgenin, the East German company Jenapharm used hyodeoxycholic acid extracted from hog bile as the sole precursor for steroid synthesis.[14]

In the 1980s, hyodeoxycholic acid was investigated for its propensity to prevent cholesterol-induced gallstones in animals fed with a lithogenic diet.[15] Another animal study determined that oral administration of HDCA leads to a decrease in LDL-cholesterol concentration, a strong stimulation of hepatic cholesterol biosynthesis and an excessive loss of cholesterol in feces.[16] Unlike ursodeoxycholic acid, which is an approved drug for the treatment of gallstones, HDCA is not marketed for any medical condition.

In supramolecular chemistry a molecular tweezer based on a hyodeoxycholic acid showed a high selectivity the towards the fluorine radical.[17]

See also

References

  1. ^ Eyssen HJ, De Pauw G, Van Eldere J (July 1999). "Formation of hyodeoxycholic acid from muricholic acid and hyocholic acid by an unidentified gram-positive rod termed HDCA-1 isolated from rat intestinal microflora". Appl. Environ. Microbiol. 65 (7): 3158–63. PMC 91470. PMID 10388717.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Haslewood GA (June 1971). "Bile salts of germ-free domestic fowl and pigs". Biochem. J. 123 (1): 15–8. PMC 1176895. PMID 5128663.
  3. ^ Sacquet E, Parquet M, Riottot M, et al. (May 1983). "Intestinal absorption, excretion, and biotransformation of hyodeoxycholic acid in man". J. Lipid Res. 24 (5): 604–13. PMID 6875384.
  4. ^ Marschall HU, Matern H, Egestad B, Matern S, Sjövall S (September 1987). "6 alpha-glucuronidation of hyodeoxycholic acid by human liver, kidney and small bowel microsomes". Biochim. Biophys. Acta. 921 (2): 392–7. doi:10.1016/0005-2760(87)90041-5. PMID 2820501.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Parquet M, Pessah M, Sacquet E, Salvat C, Raizman A, Infante R (September 1985). "Glucuronidation of bile acids in human liver, intestine and kidney. An in vitro study on hyodeoxycholic acid". FEBS Lett. 189 (2): 183–7. doi:10.1016/0014-5793(85)81020-6. PMID 3930288.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Matern H, Lappas N, Matern S (September 1991). "Isolation and characterization of hyodeoxycholic-acid: UDP-glucuronosyltransferase from human liver". Eur. J. Biochem. 200 (2): 393–400. doi:10.1111/j.1432-1033.1991.tb16197.x. PMID 1909626.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Pillot T, Ouzzine M, Fournel-Gigleux S, et al. (December 1993). "Glucuronidation of hyodeoxycholic acid in human liver. Evidence for a selective role of UDP-glucuronosyltransferase 2B4". J. Biol. Chem. 268 (34): 25636–42. PMID 8244999.
  8. ^ Mackenzie P, Little JM, Radominska-Pandya A (February 2003). "Glucosidation of hyodeoxycholic acid by UDP-glucuronosyltransferase 2B7". Biochem. Pharmacol. 65 (3): 417–21. doi:10.1016/S0006-2952(02)01522-8. PMID 12527334.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Barre L, Fournel-Gigleux S, Finel M, Netter P, Magdalou J, Ouzzine M (March 2007). "Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33". FEBS J. 274 (5): 1256–64. doi:10.1111/j.1742-4658.2007.05670.x. PMID 17263731.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Powell AA, LaRue JM, Batta AK, Martinez JD (June 2001). "Bile acid hydrophobicity is correlated with induction of apoptosis and/or growth arrest in HCT116 cells". Biochem. J. 356 (Pt 2): 481–6. doi:10.1042/0264-6021:3560481. PMC 1221859. PMID 11368775.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Powell AA, Akare S, Qi W, et al. (2006). "Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity". BMC Cancer. 6 (1): 219. doi:10.1186/1471-2407-6-219. PMC 1574338. PMID 16948850.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ Marker, Russell E.; Krueger, John (1940). "Progesterone from Hyodesoxycholic Acid". JACS. 62 (1): 79. doi:10.1021/ja01858a019.
  13. ^ Trickey, E. Bruce (1950). "Separation of the Acids of Hog Bile". JACS. 72 (8): 3474. doi:10.1021/ja01164a042.
  14. ^ Schwarz S, Onken D, Schubert A (July 1999). "The steroid story of Jenapharm: from the late 1940s to the early 1970s". Steroids. 64 (7): 439–45. doi:10.1016/S0039-128X(99)00003-3. PMID 10443899.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Singhal AK, Cohen BI, Mosbach EH, et al. (June 1984). "Prevention of cholesterol-induced gallstones by hyodeoxycholic acid in the prairie dog". J. Lipid Res. 25 (6): 539–49. PMID 6747458.
  16. ^ Cohen-Solal C, Parquet M, Férézou J, Sérougne C, Lutton C (July 1995). "Effects of hyodeoxycholic acid and alpha-hyocholic acid, two 6 alpha-hydroxylated bile acids, on cholesterol and bile acid metabolism in the hamster". Biochim. Biophys. Acta. 1257 (2): 189–97. doi:10.1016/0005-2760(95)00073-L. PMID 7619860.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Kim, K; Kim, H (2005). "A hyodeoxycholic acid-based molecular tweezer: a highly selective fluoride anion receptor". Tetrahedron. 61 (52): 12366. doi:10.1016/j.tet.2005.09.082.
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