Hyodeoxycholic acid
Encyclopedia
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.
rod
—termed HDCA-1—from several isomers of hyocholic acid and muricholic acid. 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. 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.
Hyodeoxycholic acid undergoes glucuronidation
in human liver and kidneys. 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 acid
s which can form hyodeoxycholic and hyocholic acids, respectively, after 6α-hydroxilation. 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. 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.
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.
. A decade later, an analysis of the composition of hog bile determined that HDCA accounted for approximately 40% of its acid contents. In the 1950s, lacking access to vegetal prescurors of steroids, like diosgenin
, the East German company Jenapharm
used hyodeoxycholic acid extracted from hog bile as the sole precursor for steroid synthesis.
In the 1980s, hyodeoxycholic acid was investigated for its propensity to prevent cholesterol-induced gallstones in animals fed with a lithogenic diet. 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. 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.
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
, one of the metabolic byproducts of intestinal bacteria. It differs from deoxycholic acid
Deoxycholic acid
Deoxycholic acid, also known as deoxycholate, cholanoic acid, and 3α,12α-dihydroxy-5β-cholanate, is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and...
in that the 6α-hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
is in the 12 position in the former. The 6α-hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
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
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
bile, and for this reason it was used industrially as precursor
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
for steroid synthesis before total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
became practical.
Metabolism
In rat intestinal microflora hyodeoxycholic acid is produced by a Gram-positiveGram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
rod
Bacilli
Bacilli refers to a taxonomic class of bacteria. It includes two orders, Bacillales and Lactobacillales, which contain several well-known pathogens like Bacillus anthracis .-Ambiguity:...
—termed HDCA-1—from several isomers of hyocholic acid and muricholic acid. 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
Germ-free animal
Germ-free animals are animals that have no microorganisms living in or on it. Such animals are raised within germ-free isolators in order to control their exposure to viral, bacterial or parasitic agents...
pigs, which supports the hypothesis that HDCA may be a primary bile acid in this species. In healthy humans only traces of HDCA have been found in urine, but in patients with cholestatic liver disease or intestinal malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
a significant amount has been found excreted.
Hyodeoxycholic acid undergoes glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
in human liver and kidneys. 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
Lithocholic acid
Lithocholic acid is a bile acid that acts as a detergent to solubilize fats for absorption. It is made from chenodeoxycholic acid by bacterial action in the colon.It has been implicated in human and experimental animal carcinogenesis....
and chenodeoxycholic acid
Chenodeoxycholic acid
Chenodeoxycholic acid is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165-167 °C. Salts of this carboxylic acid are called chenodeoxycholates...
s which can form hyodeoxycholic and hyocholic acids, respectively, after 6α-hydroxilation. The enzyme family responsible for glucosidation of hyodeoxycholic acid in human liver is UDP-glucuronosyltransferase. Both the UGT2B4
UGT2B4
UDP glucuronosyltransferase 2 family, polypeptide B4, also known as UGT2B4, is an enzyme that in humans is encoded by the UGT2B4 gene.- Function :...
and UGT2B7
UGT2B7
UGT2B7 is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain...
isoforms are able to glucuronidate HDCA. 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.
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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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.
Applications
It was known since 1939 that HDCA could be used to synthesize progesteroneProgesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
. A decade later, an analysis of the composition of hog bile determined that HDCA accounted for approximately 40% of its acid contents. In the 1950s, lacking access to vegetal prescurors of steroids, like diosgenin
Diosgenin
Diosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
, the East German company Jenapharm
Jenapharm
Jenapharm is a pharmaceutical company from Jena, Germany. Founded in 1950 in East Germany, the company focused from the beginning on the production and development of steroids...
used hyodeoxycholic acid extracted from hog bile as the sole precursor for steroid synthesis.
In the 1980s, hyodeoxycholic acid was investigated for its propensity to prevent cholesterol-induced gallstones in animals fed with a lithogenic diet. 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. Unlike ursodeoxycholic acid, which is an approved drug for the treatment of gallstones, HDCA is not marketed for any medical condition.
In supramolecular chemistry
Supramolecular chemistry
Supramolecular chemistry refers to the area of chemistry beyond the molecules and focuses on the chemical systems made up of a discrete number of assembled molecular subunits or components...
a molecular tweezer
Molecular tweezer
Molecular tweezers, sometimes termed molecular clips, are noncyclic macro molecular complexes with open cavities capable of binding guests. The term "molecular tweezer" was first used by Howard J. Whitlock, but the class of hosts was developed and popularized by Steven C. Zimmerman in the mid-1980s...
based on a hyodeoxycholic acid showed a high selectivity the towards the fluorine
Fluorine
Fluorine is the chemical element with atomic number 9, represented by the symbol F. It is the lightest element of the halogen column of the periodic table and has a single stable isotope, fluorine-19. At standard pressure and temperature, fluorine is a pale yellow gas composed of diatomic...
radical.
See also
- chenodeoxycholic acidChenodeoxycholic acidChenodeoxycholic acid is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165-167 °C. Salts of this carboxylic acid are called chenodeoxycholates...
for a similar molecular tweezer which exhibits different selectivity