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bile acid

Wednesday 4 June 2003

Definition: Bile acids (also known as bile salts) are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids conjugated to glycine or taurine. In the common biomedical literature, the terms “bile acids” or “bile salts” are generally used to denote the so-called “modern” bile acids.

They are present in the bile acid pool of primitive (e.g. coelacanth and sharks) and less primitive (e.g. reptiles and amphibians) vertebrates.

In humans, taurocholic acid, and glycocholic acid (derivatives of cholic acid) represent approximately eighty percent of all bile acids.

The two major bile acids are cholic acid, and chenodeoxycholic acid. They, their glycine and taurine conjugates, and their 7-alpha-dehydroxylated derivatives (deoxycholic acid and lithocholic acid) are all found in human intestinal bile.

Biosynthesis

Bile acids are made in the liver by the cytochrome P450-mediated oxidation of cholesterol. They are conjugated with the amino acids taurine or glycine, or with a sulfate or a glucuronide, and are then stored in the gallbladder.

In humans, the rate limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase.

The term bile acid refers to the conjugated form. In the duodenum’s alkaline environment, the bile acids become bile salts as a result of the basic pH and the relative pKa of the acids. Bile salt refers to the ionic form of the secreted bile acid.

Synthesis of bile acids is a major consumer of cholesterol in most species (other than humans).

The body produces about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis.

Chemical structure

Bile acids have 24 carbon atoms and are abbreviated as C24 bile acids, in contraposition to “primitive” bile acids, which have 25-27 carbon atoms (C27, C26, C25 bile acids).

In higher vertebrates, C24 bile acids constitute a major part of the bile, and in human bile, these compounds are almost completely in conjugated form with either glycine (75%) or taurine (25%). Under physiological conditions, conjugation increases their water-solubility.

Bile salts have a unique and fascinating molecular structure derived from a saturated tetracyclic hydrocarbon perhydrocyclopentanophenanthrene system, usually known as the steroid nucleus.

The steroid nucleus is also the main carbon skeleton of other families of compounds such as brassinosteroids, ubiquitously distributed throughout the plant kingdom, hopanoids, commonly used as biomarkers in organic geochemistry, triterpenoids, and hormones.

The steroid nucleus consists of three six-member rings (A, B and C) and a five-member ring (D), with a curved (beaked) or flat structure (depending on a cis- or trans-fused configuration between the A and B rings).

In mammals, the nucleus is almost invariably 5β (A/B junction in cis configuration), while in lower vertebrates, some bile acids, known as allo-bile acids, exhibit an A/B trans-fusion. There are 11 chiral carbon atoms. Bile acid molecules are approximately 20 å long, with an average radius of about 3.5 å.

Types

Bile salts constitute a large family of molecules, composed of a steroid structure with four rings, a five or eight carbon side-chain terminating in a carboxylic acid, and the presence and orientation of different numbers of hydroxyl groups.

The four rings are labeled from left to right (as commonly drawn) A, B, C, and D, with the D-ring being smaller by one carbon than the other three. The hydroxyl groups have a choice of being in 2 positions, either up (or out) termed beta (often drawn by convention as a solid line), or down, termed alpha (seen as a dashed line in drawings).

All bile acids have a hydroxyl group on position 3, which was derived from the parent molecule, cholesterol. In cholesterol, the 4 steroid rings are flat and the position of the 3-hydroxyl is beta.

In many species, the initial step in the formation of a bile acid is the addition of a 7-alpha hydroxyl group.

Subsequently, in the conversion from cholesterol to a bile acid, the junction between the first two steroid rings (A and B) is altered, making the molecule bent, and in this process, the 3-hydroxyl is converted to the alpha orientation.

Thus, the default simplest bile acid (of 24 carbons) has two hydroxyl groups at positions 3-alpha and 7-alpha. The chemical name for this compound is 3-alpha,7-alpha-dihydroxy-5-beta-cholan-24-oic acid, or as it is commonly known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived.

Another bile acid, cholic acid (with 3 hydroxyl groups) had already been described, so the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made the new bile acid a "deoxycholic acid" in that it had one less hydroxyl group than cholic acid.

The 5-beta portion of the name denotes the orientation of the junction between rings A and B of the steroid nucleus (in this case, they are bent).

The term "cholan" denotes a particular steroid structure of 24 carbons, and the "24-oic acid" indicates that the carboxylic acid is found at position 24, which happens to be at the end of the side-chain.

Chenodeoxycholic acid is made by many species, and is quite a functional bile acid. Its chief drawback lies in the ability of intestinal bacteria to remove the 7-alpha hydroxyl group, a process termed dehydroxylation. The resulting bile acid has only a 3-alpha hydroxyl group and is termed lithocholic acid (litho = stone).

It is poorly water-soluble and rather toxic to cells. Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids. As a result, chenodeoxycholic acid is a primary bile acid, and lithocholic acid is a secondary bile acid.

To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid.

In this manner, the subsequent removal of the 7-alpha hydroxyl group by intestinal bacteria will result in a less toxic, still functional dihydroxy bile acid.

Over the course of vertebrate evolution, a number of positions have been chosen for placement of the third hydroxyl group. Initially, the 16-alpha position was favored, particularly in birds. Later, this position was superseded by a large number of species selecting position 12-alpha.

Primates (including humans) utilize 12-alpha for their third hydroxyl group position. The resulting primary bile acid in humans is 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oic acid, or as it is commonly called, cholic acid.

In the intestine, cholic acid is dehydroxylated to form the dihydroxy bile acid deoxycholic acid. In many vertebrate orders still subject to speciation, new species are discarding 12-alpha hydroxylation in favor of a hydroxy group on position 23 of the side-chain.

It should be noted that vertebrate families and species exist that have experimented with and utilize just about every position imaginable on the steroid nucleus and side-chain.

In humans, the most important bile acids are cholic acid, deoxycholic acid, and chenodeoxycholic acid.

Conjugaison

Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine.

Conjugation increases their water solubility, preventing passive re-absorption once secreted into the small intestine.

As a result, the concentration of bile acids in the small intestine can stay high enough to form micelles and solubilize lipids.

The term "critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles.

Enterohepatic circulation

In total about 20-30 grams of bile acids are secreted into the intestine daily; about 90% of excreted bile acids are reabsorbed (by active transport in the ileum) and recycled. This is referred to as the enterohepatic circulation.

Functions

Traditionally considered as digestive molecules whose main function is to help in the emulsion and absorption of dietary fats and liposoluble vitamins, bile acids are beginning to be considered more versatile molecules than previously believed.

Bile acid’s main function is to facilitate the formation of micelles, which promotes dietary fat processing.

Bile acid also serves the purpose of breaking down fats. Upon eating a meal containing fat, the contents of the gallbladder are secreted into the intestine.

Bile acids serve multiple functions, which include: eliminating cholesterol from the body; driving the flow of bile to eliminate catabolites from the liver; emulsifying lipids and fat soluble vitamins in the intestine; and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract. Bile is also used to break down fat goblets into tiny droplets.

Pathology

- anomalies of bile acids

See also

- bile acid metabolism

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