How substances move through the body: solutions, membranes and compartments
Whether a substance dissolves in water or in fat decides where it can go in the body. Sheets of cells and the membranes around and within cells divide the body into compartments. A molecule that slips through a cell membrane is hard to carry in the blood, and one that travels easily in the blood has trouble crossing membranes. A molecule's charge and polarity predict whether it dissolves in water or in fat, and membrane transport proteins, endocytosis and exocytosis move what cannot cross a membrane on its own.
Six principles of transport
Every living thing has a metabolism, a set of chemical reactions. For those reactions to happen, some chemicals must enter the organism and others must leave it. Understanding the transport of substances in the body takes six basic principles. Three were known even in ancient times: water runs downhill, oil and water do not mix, and passing through a wall takes a doorway. The other three were discovered only after the invention of the microscope: blood goes round and round, all living things are made of cells and the materials cells produce, and every cell is surrounded by an oily membrane that controls the flow of materials into and out of it.
The body's compartments
To enter the body, a substance must pass between or through the cells that line its outer and inner surfaces, such as the skin or the linings of the lungs and gastrointestinal tract. These sheets of cells, the membrane around each cell and the membranes that enclose spaces within cells can be seen as barriers that define compartments. The chief compartments are the exterior of the body, which includes the inside of the gastrointestinal tract and the air spaces of the lungs; the blood plasma; the extracellular space, the fluid around the cells; the intracellular space, the fluid within each cell membrane; and the brain, walled off from the rest of the body by the blood-brain barrier.
A barrier is permeable if it lets something pass, and some barriers are more permeable than others. In most of the body, the capillaries have tiny gaps or pores between the endothelial cells that line their walls, and these pores let many substances pass from the blood into the tissue. In the brain, those endothelial cells are held together by tight junctions, so a substance entering the brain must pass through the cells themselves rather than slip between them.
Ions and polar bonds
An ion is an atom or molecule with a net positive or negative charge. A cation, pronounced "cat-eye-on", is positive because it has more protons than electrons, and an anion is negative because it has more electrons than protons. In an ionic bond, one or more electrons pass from one atom or molecule to another. For example, sodium gives up an electron to become a sodium ion (Na+), chlorine takes one to become a chloride ion (Cl−), and the two ions can then be held together by electrostatic forces.
In a covalent bond, two atoms share a pair of electrons evenly. Such bonds are nonpolar and form between atoms with a similar electronegativity, their ability to attract electrons. They form between two atoms of the same element, such as two carbons or two oxygens, and between atoms of different elements with similar electronegativity, such as carbon and hydrogen. A polar bond is almost a hybrid of the two: the pair of electrons is shared but pulled more strongly towards the more electronegative atom, so the bond has a positive pole and a negative pole. Fluorine is the most electronegative, followed by oxygen and then nitrogen, so a bond between oxygen and carbon or hydrogen is polar, with its negative pole near the oxygen. An ionic or polar bond can sometimes split into a cation and an anion, as a water molecule (H2O) can split into a hydrogen ion (H+) and a hydroxide ion (OH−). This splitting is called ionic dissociation.
A bond's polarity is measured by its dipole moment, a vector with both a magnitude and a direction. A molecule's dipole moment is the vector sum of its bonds' moments, so two polar bonds of equal magnitude that point in opposite directions cancel out and leave the molecule nonpolar. Carbon dioxide is linear, so the moments of its two double bonds cancel, and it is nonpolar. Water is V-shaped, so the moments of its two bonds do not cancel, and it is strongly polar. Oxygen (O2) is nonpolar because its bonds are nonpolar, and ethanol and glucose are polar.
Hydrophilic, hydrophobic and amphiphilic substances
Substances that dissolve easily in water or are attracted to it are hydrophilic, "water loving". Substances that dissolve poorly in water and seem to repel it are hydrophobic, "water fearing". Molecules with at least one hydrophilic and at least one hydrophobic domain, or region, are amphiphilic, "loving both". Chemists can accurately predict which of the three a chemical species is from its net electrical charge and its electrostatic potential map, which shows how the charge is distributed around the molecule. Ions, ionic compounds and polar molecules are hydrophilic, and nonpolar molecules are hydrophobic. Amphiphilic molecules, also called amphipathic, have at least one polar and at least one nonpolar domain.
Because water molecules are polar, hydrogen bonds join them to one another. A hydrogen bond is the weak electrostatic attraction between a hydrogen atom bound to a highly electronegative atom, which is fluorine, oxygen or nitrogen, and a nearby highly electronegative atom. These bonds explain why water stays liquid at room temperature and atmospheric pressure while other compounds of similar molecular weight are gases, and why its boiling point is so high compared with other molecules of similar molecular weight. The same polarity strongly attracts water to ions such as Na+ and Cl− and to polar molecules such as glucose, which is why ionic and polar compounds are hydrophilic.
An ionic compound is highly soluble in water if its cations and anions attract each other less strongly than water pulls on them. Likewise, how soluble a polar compound is depends on whether water can pull its molecules apart from one another. Where water pulls a compound apart into ions, the solution contains charged particles and so conducts electricity. That is why a solution of table salt, an ionic compound, conducts electricity and a solution of glucose, a polar compound, does not. The solutes that let a water-based solution conduct electricity are called electrolytes.
Oil and water do not mix because water molecules attract one another so strongly that they tend to squeeze out nonpolar molecules, such as those of oils. The nonpolar molecules are held to one another by weak forces called van der Waals forces, and this is why nonpolar compounds are hydrophobic. Hydrophobic organic compounds of biological origin are often called lipids, among them fats, waxes, sterols and the fat-soluble vitamins. Hydrophobic compounds tend to dissolve in nonpolar solvents such as chloroform and ether, and hydrophilic compounds generally do not, which is why salt and sugar do not dissolve in gasoline.
Amphiphiles and the semipermeable membrane
The phospholipids that make up cell membranes are amphiphiles. A phospholipid consists of a glycerol molecule bonded to one phosphate group, the hydrophilic head, and two fatty acids, the hydrophobic tails. In water, amphiphiles come together into aggregates: a ball such as a micelle, a hollow shell such as a liposome, or a bilayer sheet such as a cell membrane. In these aggregates the heads face the water, and the tails cluster with one another and sometimes with other hydrophobic substances.
An amphiphile can form a hydrophilic surface around a particle or droplet of hydrophobic material, and so lets that material mix with water. This is how soap works. The same principle is important in digesting fats, in carrying fatty substances such as fat and cholesterol in the blood, and in developing targeted drug delivery systems.
Because the cell membrane is oily, fat-soluble substances such as oxygen, carbon dioxide and lipids can diffuse right through it, as can nonpolar molecules generally. The membrane is an effective barrier to ions and large polar molecules, but some small polar molecules, such as water and ethanol, can seep through. So the cell membrane is semipermeable: water can pass through it, but ions and large polar molecules cannot.
The oil-and-water dilemma
Blood is a water-based fluid, so a substance carried in it must be able to mix with water, and this poses a dilemma. Substances that dissolve in oil can easily pass through cell membranes, into the bloodstream and from the blood into the brain, but they are hard to carry in the blood. Substances that are easy to carry in the blood often have a hard time crossing cell membranes because they cannot dissolve in oil, so they have a hard time getting into the blood plasma, into cells and into the brain. In other words, fat-soluble molecules pass easily into and out of cells but have a hard time reaching them, and water-soluble molecules reach cells easily but have a hard time getting into or out of them.
Ions and polar molecules mix easily with water, so they are easily carried in the blood and diffuse through the fluid that bathes the cells. But ions and large polar molecules cannot easily pass through the lipid bilayer around each cell, so they have difficulty passing from one compartment to another unless they can pass through a membrane transport protein.
To solve this dilemma, the body makes substances, among them phospholipids and various proteins, that can mix with water or oil. Transport proteins let fat-soluble molecules, which cannot easily mix with water otherwise, be carried in the blood, and membrane transport proteins embedded in cell membranes let water-soluble substances cross those membranes. Proteins can do this because they are long chains of up to 20 different amino acids. Each protein has a predictable shape that depends on its sequence of amino acids, and that sequence is encoded in DNA in the gene for the protein. Each amino acid has a unique side chain, some attracted to water and some to fat, so a protein may have some domains attracted to water and others attracted to fat.
Membrane transport proteins
Ions and large polar molecules such as glucose cannot flow into or out of a cell unless the membrane has a doorway, an opening made by a membrane transport protein. The protein's hydrophobic domains anchor it in the membrane, and its hydrophilic domains face or even reach into the watery environments inside and outside the cell.
Membrane transport proteins fall into two broad categories, passive and active. Passive ones simply let a substance diffuse into or out of the cell. So they let a substance flow, in net, from higher to lower concentration, down a concentration gradient, and let charged particles flow towards particles of the opposite charge, up or down a voltage gradient. Some passive transport proteins can open or close in response to a specific stimulus, a change in voltage, the binding of a ligand or, in the cochlea of the ear, pressure, and so can regulate what passes into or out of the cell. In passive transport the net flow is always downhill with respect to the electrochemical gradient.
Three types of membrane transport protein are involved in passive transport: uniporters, symporters and antiporters. Uniporters let only one substance cross the membrane. Co-transporters let two or more different substances cross, and symporters carry them in the same direction. For example, the Na+/glucose symporter lets a sodium ion and a glucose molecule flow into the cell at the same time. Antiporters carry two substances in opposite directions. An antiporter lets one substance flow passively down its electrochemical gradient, and the energy of that flow drives the other uphill against its own. For example, the sodium–calcium exchanger removes calcium from cells: by letting three sodium ions in, it gains enough energy to push one calcium ion out.
Active transport, by contrast, uses the cell's metabolic energy to move substances uphill against their electrochemical gradient. The cell stores this energy as adenosine triphosphate (ATP). For example, the sodium–potassium pump uses the energy it gets from removing a phosphate group from ATP to drive three sodium ions out of the cell, and then lets two potassium ions flow in, in response to their electrochemical gradient.
Endocytosis and exocytosis
Endocytosis, bringing something into the cell, and exocytosis, expelling something from it, are other ways for a cell to move substances across its membrane. They are particularly important for polar molecules too large to pass through a membrane transport protein. Cells can pull fluid in by pinocytosis, "cell drinking", and specific materials by receptor-mediated endocytosis, in which the material binds a receptor on the cell surface. In both, the membrane forms a pit that deepens into a pocket around the material, and the pocket is pinched off as a membrane-bound vesicle inside the cell.
Some cells, including some white blood cells, can also bring large particles in by phagocytosis, which occurs only in animal cells. In phagocytosis the membrane reaches out to surround a particle such as a bacterium, and the pouch is brought into the cell and pinched off as a membrane-bound phagosome or food vacuole. Prokaryotes such as bacteria generally cannot perform phagocytosis, partly because they have a rigid cell wall and partly because they lack the cytoskeleton, the internal structure the movement needs. The material in the vacuoles that endocytosis forms can then be digested by enzymes before it is released into the cytosol.
Exocytosis is endocytosis in reverse. A secretory vesicle is brought to the surface of the cell, its membrane fuses with the cell membrane, and its contents are released into the extracellular space.