![Enterohepatic](https://upload.wikimedia.org/wikipedia/commons/1/17/Enterohepatic.svg)
Enterohepatic circulation refers to the circulation of
biliary acids,
bilirubin, drugs or other substances from the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
to the
bile, followed by entry into the
small intestine, absorption by the
enterocyte and transport back to the liver. Enterohepatic circulation is an especially important concept in the field of
toxicology
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating e ...
as many
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
undergo this process causing repeated liver damage.
Biliary acids
The circuit
Hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
s
metabolize
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
to
cholic acid
Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Chol ...
and
chenodeoxycholic acid
Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the mai ...
. These
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
-
soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubi ...
bile acids are conjugated (reversibly attached) mainly to
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
or
taurine
Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. I ...
molecules to form
water
Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...
soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubi ...
primary conjugated bile acids, sometimes called "bile salts". These bile acids travel to the gall bladder during the interdigestive phase for storage and to the descending part of the
duodenum via the
common bile duct
The common bile duct, sometimes abbreviated as CBD, is a duct in the gastrointestinal tract of organisms that have a gallbladder. It is formed by the confluence of the common hepatic duct and cystic duct and terminates by uniting with pancrea ...
through the major duodenal
papilla during digestion. 95% of the bile acids which are delivered to the duodenum will be recycled by the enterohepatic circulation.
Due to the pH of the small intestine, most of the bile acids are ionized and mostly occur as their sodium salts which are then called “primary conjugated bile salts.” In the lower small intestine and
colon, bacteria dehydroxylate some of the primary bile salts to form secondary conjugated bile salts (which are still water-soluble). Along the proximal and distal
ileum
The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...
, these conjugated primary bile salts are reabsorbed actively into hepatic portal circulation. Bacteria deconjugate some of the primary and secondary conjugated bile salts back to lipid-soluble bile acids, which are passively absorbed into hepatic portal circulation. Finally, the conjugated bile acids which remained un-ionized conjugated bile acids are passively absorbed.
Venous blood from the ileum goes straight into the portal vein and then into the
liver sinusoid
A liver sinusoid is a type of capillary known as a sinusoidal capillary, discontinuous capillary or sinusoid, that is similar to a fenestrated capillary, having discontinuous endothelium that serves as a location for mixing of the oxygen-rich blo ...
s. There, hepatocytes extract bile acids very efficiently, and little escapes the healthy liver into systemic circulation.
The net effect of enterohepatic recirculation is that each bile salt molecule is reused about 20 times, often multiple times during a single digestive phase.
Function
The presence of biliary acids in the intestines helps in
absorption of fats and other substances.
Bilirubin
Bilirubin is conjugated with
glucuronic acid in the liver by the enzyme
glucuronyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This i ...
, making it soluble in water. Much of it goes into the bile and thus out into the small intestine. Although 20% of the secreted bilirubinoid bile is reabsorbed by the small intestine, conjugated bilirubin is not reabsorbed in small intestine. All conjugated bilirubin in the large intestine is metabolised by colonic bacteria to
urobilinogen
Urobilinogen is a colorless by-product of bilirubin reduction. It is formed in the intestines by bacterial action on bilirubin. About half of the urobilinogen formed is reabsorbed and taken up via the portal vein to the liver, enters circulation an ...
, which is then further oxidized to
urobilin
Urobilin or urochrome is the chemical primarily responsible for the yellow color of urine. It is a linear tetrapyrrole compound that, along with the related colorless compound urobilinogen, are degradation products of the cyclic tetrapyrrole heme ...
and
stercobilin
Stercobilin is a tetrapyrrolic bile pigment and is one end-product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: A cellular and molecular approach, 2005. 984-986. Elsevier Saunders, United States. Kay IT, Weimer M, Watson CJ (1963) ...
. Urobilin, stercobilin and their degradation products give feces its brown color. However, just like bile, some of the urobilinogen reabsorbed is resecreted in the bile which is also part of enterohepatic circulation. The rest of the reabsorbed urobilinogen is excreted in the urine where it is converted to an oxidized form,
urobilin
Urobilin or urochrome is the chemical primarily responsible for the yellow color of urine. It is a linear tetrapyrrole compound that, along with the related colorless compound urobilinogen, are degradation products of the cyclic tetrapyrrole heme ...
, which gives urine its characteristic yellow color.
Drugs
Chloramphenicol, aspirin, paracetamol, diazepam, lorazepam, morphine, metronidazole.
Not only drugs but endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this pathway.
Enterohepatic circulation of drugs describes the process by which drugs are conjugated to glucuronic acid in the liver, excreted into bile, metabolized back into the free drug by intestinal bacteria, and the drug is then reabsorbed into plasma. For many drugs that undergo this process, lower doses of drugs can be therapeutically effective because elimination is reduced by the 'recycling' of the drug. But for a small number of drugs that are very toxic to the intestine (e.g. irinotecan), these molecules which would not otherwise be very toxic can become so because of this process, and therefore inhibition of this step can be protective. For the majority of drugs which undergo enterohepatic circulation that are not toxic to the intestine, inhibition of this process leads to a reduction of the levels of drug and reduced therapeutic effect. For example, antibiotics that kill gut bacteria often reduce enterohepatic drug circulation and this requires a temporary increase of the drug's dose until the antibiotic use is discontinued and the gut repopulates with bacteria. This effect of antibiotics on enterohepatic circulation of other drugs is one of several types of drug interactions.
Pharmacokinetic Models of enterohepatic circulation
Pharmacokinetic models of the enterohepatic circulation process has been summarized in a recent article.
[Okour, M. & Brundage, R.C. Curr Pharmacol Rep (2017) 3: 301. https://doi.org/10.1007/s40495-017-0096-z]
See also
*
Enteroenteric circulation
References
{{Portal bar, Biology, Medicine
Hepatology
Angiology
Digestive system