From my book, Herbs Demystified
illustrations by Tim Erskine
Herbal Interactions with Receptors and Enzymes
You hear that an herbal chemical acts on your brain or your heart, but how exactly does it do this? Every cell your body is awash in a constant stream of chemical signals. Some of these chemicals are homemade by your own body, and others are foreign, like chemicals from an herb. Yet each of your cells only responds to some chemicals, and ignores the rest. How does each cell pick which chemicals to respond to?
Chemicals from herbs often mediate effects on your cells by temporarily fitting into either receptors or enzymes. Like a key fitting into a lock, particular herbal chemicals can only fit into particular receptors or enzymes. They do this using the attractive version of the electrostatic force.
Receptors and enzymes are types of proteins. (If you want to know more about proteins in general, see “More details about proteins, if you really want to know”, below.) These proteins have specific shapes, with pocket-like indentations that are analogous to a keyhole. When an herbal chemical fits into the keyhole, so to speak, these proteins in turn have an effect on your cells and your body.
Receptors and enzymes both accept certain chemicals like locks accepting keys, but receptors function differently from enzymes. Receptors are like on/off switches for various actions in a cell. Each cell has an assortment of switches with different jobs. When a receptor switch encounters a chemical “key” that binds to it, the receptor inhibits or activates certain functions in the cell.
Enzymes, on the other hand, are found everywhere in your body, both associated with your cells and existing outside of them. Enzymes transform other chemicals. Our enzymes help us transform one molecule into a different one. When an herbal chemical binds to an enzyme, the herbal chemical may be transformed into a different one. too. Sometimes an herbal molecule prevents one of your enzymes from performing its usual transformation on another molecule.
The Bottom Line
Some herbal chemicals are attracted by the electrostatic force to particular receptors or enzymes, and temporarily fit into them like a key fits into a lock. If an herbal chemical binds to a cell’s receptor, it inhibits or activates functions in the cell. If an herbal chemical binds to an enzyme, it might get changed by the enzyme, or affect the enzyme’s ability to alter a different chemical.
More details about proteins, if you really want to know
Proteins are chains of amino acids folded up into a functional shape.
Proteins are molecules that are made of chains of smaller molecules called amino acids, bonded and strung together like beads on a string. Since twenty different amino acids are used to make proteins, you can imagine the resultant polypeptide string as a strand of hundreds of beads strung together, with twenty different types of “beads” strung in a specific sequence unique to each protein. This strand folds into a particular shape required for the proteins’ function.
Each gene carries information of what the amino acid sequence is for one protein.
The information on how to make a particular protein passively rests in a different structure in a cell, called a gene. A mulitude of different genes, each with instructions on how to make different proteins, lie in strips as part of a larger molecule, DNA. The purpose of a specific gene is to give information about what the sequence of amino acids is for a protein, so different genes determine which “beads” get strung together in which order to make a certain protein. If you were to point randomly to a strip of DNA that harbored a gene, you would be pointing to the cell’s instructions for making one particular protein. Each gene has instructions for how to make a different protein. Different cells “read” different gene instructions, and that is why you have different cell types—they make different proteins. The cell reads the gene’s instructions using enzymes that zip along the DNA strip, making the equivalent of photocopies of the information in the form of RNA molecules, which are carried off to another part of the cell for the protein’s construction to commence. So, if you have a genetic disorder, you have a gene with faulty instructions on how to make one of your proteins. The disease is cause by the dysfunction of the incorrectly constructed protein that the faulty gene codes for. (This is a bit oversimplified, for example, many genes cooperate to make protein products that unite to become the final product, but the general theme is true.) Some herbal molecules can influence this protein-making process by influencing the enzymes that read various genes. This can result in either increased or decreased construction of a particular proteins.
The amino acid’s attractions for each other causes the protein to fold up into the shape required for its activity.
However, even with the correct sequence of amino acids, a polypeptide string is not technically a protein and will not function properly in your body, unless it has the right shape. The beads, or amino acids, have different degrees of electrostatic attraction for each other, depending whether they are polar amino acids or nonpolar ones. If you had a necklace with sticky beads, the necklace would fold up into a clump. For proteins, the shape of this clump is not random. A polypeptide chain has to fold up into its characteristic shape in order to be a functioning protein. The locations of the beads on the string and their varying degrees of stickiness for each other helps the string fold up into the correct shape.
the chain folds because of differing attractions in it
A polypeptide chain made of a chain of amino acids folds up into a protein with a specific shape because of the varying attractions of different amino acids for each other.
Proteins do many different things.
Proteins have many diverse functions. Some proteins are, like bricks and mortar, just structural building materials. These proteins don’t do much except create walls and channels and other cellular architecture. For example, collagen proteins are tough fibers, and like “rebar” in concrete, it gives your tissues strength. Elastin proteins are spongy proteins with flexible chains, and like little rubber bands, they give your tissues the ability to spring back into place.
Other proteins use energy to move. Actin and myosin are protein filaments in muscle cells which slide along one another, causing your muscles to contract. Some proteins tote other chemicals around, like hemoglobin in red blood cells, which transports oxygen through your blood.
Still other proteins, called antibodies, protect you from microscopic strangers and oddballs, like bacteria, viruses, and cancer cells. A fancier term for antibody is “immunoglobulin”, but they are the same thing. These proteins have probing ends that ideally electrostatically bind to strange and potentially dangerous things, and less ideally, they can attack yourself in cases of friendly fire known as “autoimmune diseases”.
Enzymes are proteins which modify other chemicals. They are unchanged, themselves, during this process, so you can view them as tiny factories designed to electrostatically bind certain ingredients, which they turn into something new. You may be most familiar with digestive enzymes, which break down large food chemicals into smaller, more digestible ones in your digestive tract, but these are only a small subset of your enzymes. All cells contain enzymes, too, and enzymes do a lot more than just digest food. Enzymes perform almost all of the chemical transformations taking place in your body.
Receptor proteins also electrostatically bind chemicals, but unlike enzymes, they do not usually change the chemicals they bind. A receptor accepts a chemical like a lock accepts a key, and this binding is like a switch that turns various functions in a cell on or off.
Herbs have proteins, and herbs affect your own proteins, too.
Herbs certainly have proteins, but your digestive tract is not kind to proteins, and rips them up into isolated amino acids. Thus, you should not expect an herbal protein to have an effect beyond your digestive tract should you eat it. Herbal chemicals can, on the other hand, affect your own proteins dramatically.
The bottom line
A protein is made of a strand of smaller molecules called amino acids. The strand folds up into a characteristic shape necessary for protein to work. Some proteins are just building materials, and others create movement or move other things around. Some disable disease-causing organisms. Enzymes are reusable proteins that change other chemicals. Receptors proteins are like “on” or “off” switches for various functions in cells. Herbal proteins are broken into amino acids if they go through your digestive tract. On the other hand, herbs can influence your own proteins.
Herbal chemicals can bind to your cell’s receptors, acting as agonists or antagonists
Receptors act as on or off switches for various jobs in a cell.
Receptors are proteins associated with cells, and different cells have different sorts of receptors. They function like on or off switches for various cellular actions. For example, insulin receptors turn on the ability to import the sugar glucose into your cells, when it binds to insulin. Other receptors turn on or off your cells’ programs to grow and divide. Herbal chemicals often interact with your receptors, which in turn may have dramatic effects on your cells. For example, some herb-receptor interactions protect your cells from cancer. Others can kill the cell.
Many receptors sit right on the surface of the cell, so an herbal chemical encounters it when it approaches the cell. External receptors are given the really obvious term “cell surface receptor.” Other receptors are inside the cell, so an herbal chemical has to penetrate the cell to interact with it, which can be extra difficult. These receptors are called “intracellular receptors”. Each of your cells has both cell surface receptors and intracellular receptors.
But how does an herbal molecule actually get these cellular switches to work? It might help to imagine a receptor protein as a three-dimensional lock, into which various chemical keys may or may not fit. Chemical keys that fit a receptor are called ligands. These keys fit into specialized pockets called receptor sites, where, based on the pocket’s size, shape, and location of charged regions inside of it, a specific chemical will be electrostatically attracted to it and temporarily fit inside it. Receptors are picky about what fits inside their pockets. Not only is a physical fit required, as with actual keys, but charges within the receptor site must line up with opposite charges on the ligand. The discrimination of the receptor for binding only particular chemicals is called its specificity. Some receptors are more picky, or specific, than others.
When the proper fit is attained, the receptor protein changes its shape slightly, in order to maximize electrostatic attractions. The receptor’s deformation, in turn, nudges some other molecules into creating a biochemical effect. The effects are usually not permanent—the electrostatic attractions of the ligand-key for the receptors active site are usually weak enough for the ligand to drift off on its own, after a while. Sometimes the cell even takes in the ligand and “eats” it—breaking it down into other chemicals.
Herbs that activate receptors are agonists.
Chemical keys that successfully get a receptor to respond to them are called agonists. Partial agonists initiate weak responses, while full agonists produce more pronounced effects on a cell. Partial agonists are found in many herbs. For example, soy, black cohosh, and red clover contain partial agonists for estrogen receptors, and they can block the more potent effects of this hormone, by their temporary occupation of estrogen’s binding site. If you are a woman suffering from menopausal symptoms, you are probably aware of the recent Women’s Health Initiative Studies, which linked conventional hormone replacement therapy for menopausal women to heart disease, stroke, and some types of cancer. Shaken by these unexpected findings, scientists are seriously searching for safer, alternative estrogen receptor agonists, including ones from these herbs.
Full agonists are also found in many herbs. A striking example is that of the Mexican “divining” sage, Salvia divinorum, which has chemicals that cling to opium receptors in your brain. Fortunately ordinary cooking sage does not have these chemicals, because they make you hallucinate.
Herbs that block receptors activity are antagonists.
Have you ever inserted a key into a lock, to have it fit, but not turn in the lock? Some chemicals do the equivalent of this: although they bind to a receptor, they can’t get it to work. They also physically block the “right key”, preventing the natural ligand from doing its job. This is a competitive antagonist, a chemical imposter obstructing the natural ligand. Non-competitive antagonists also inhibit receptor functioning, but do so in a more roundabout way, without competing with the natural ligand for its binding site. Herbal receptor antagonists are extremely common.
You might even consume herbal receptor antagonists daily, if you drink tea, coffee, or eat chocolate. These plant-derived goodies contain chemicals that inhibit the adenosine receptor. Adenosine makes you sleepy. As you spend energy throughout the day, adenosine builds up in your body. Adenosine is a leftover piece of a larger chemical (adenosine triphosphate) that is degraded to give you energy. The more energy you spend, the more adenosine builds up in your brain. The binding of adenosine to its receptors in your brain causes your nerves to slow down, making you groggy.
Early in human history, we stumbled across plants that contain adenosine look-alikes, and treasured them. We now routinely use them to undermine this elegant connection between energy expenditure and tiredness. Coffee, tea, and chocolate are the most popular sources for adenosine impersonators, called methylxanthines. You are probably more familiar with the most renowned methylxanthine, caffeine, but theophylline and theobromine also occur in varying amounts in coffee, tea, and chocolate, and they work the same way. Methylxanthines are found in many other plants, too, like the South American herbs mate’ and guarana. Because methylxanthines resemble adenosine, they park inside your brains’ adenosine’s receptors, preventing adenosine from binding. When adenosine can’t bind, it can’t make you sleepy.
The effect of an herbal agonist or antagonist can be good or bad, depending on what function it affects, and how much it affects it.
Is it bad to play with your receptors? Sometimes it helps. It really depends on which receptor you mess with, and how much you are affecting it. The hallucinogenic divining sage doesn’t seem like the brightest idea, especially if you are driving or working in a factory with lots of sharp blades whirling around. However, other plants that interact with the opium receptor in a more refined manner could act as useful pain relievers. The adenosine receptor antagonists from coffee, chocolate, and tea, appear fairly harmless for humans, (but not for pets—see “Your pet has different receptors and enzymes”). Our perhaps puritanical need to vilify such alluring substances has continuously been thwarted by years of research on these beloved comestibles. These studies show that, though their methylxanthines can make you jittery and sleepless at worst, they are relatively benign, and might even do good things, like decrease your risk of Parkinson’s disease. Coffee, tea, and chocolate also contain beneficial plant antioxidants, so perhaps less guilt is required when you consume them. Overall, you should judge an herbal ligand by the receptor switch it that it affects, and how much it affects it.
The bottom line
An herbal chemical can temporarily bind to a cell’s receptor, which initiates or halts an activity in the cell. Chemicals that act on receptors are agonists; effective ones are full agonists and weaker ones are partial agonists. Chemicals that block a receptor’s action are antagonists. Whether the effect is beneficial or not depends on what receptor is being affected, and how much it is being affected.
Herbal chemicals affect your enzymes, too.
Enzymes are like little machines that transform other chemicals.
Enzymes are proteins that can be found everywhere in your body, both inside cells and existing outside of them. Most enzyme names end in “-ase”, by the way, so if you see a name ending in “-ase”, you can bet it’s an enzyme. Enzymes transform other chemicals, but remain unchanged, themselves. Thus, they are like tiny chemical processing machines. A drill does not change when it drills a hole in something, so can be used repeatedly. Likewise, the same enzyme can transform many chemicals of one type into chemicals of another type, one at a time, like a machine on an assembly line. And like machines on assembly lines, different enzymes have different tasks, each carrying out various chemical transformations. Sometimes herbal chemicals are worked on by these tiny machines and changed into something new. In other cases, herbal chemicals affect the machine’s function, so to speak, either hampering or enhancing their ability to transform other chemicals.
But how do your enzymes work? Like receptors, enzymes have similar pockets, called active sites, which electrostatically attract chemicals with the right fit, again like a key fitting into a lock. While a receptors’ keyhole accepts a ligand, an enzyme’s keyhole accept its substrate. So, a substrate is a chemical that a particular enzyme works on, and it is common for herbal chemicals to become substrates for an enzyme. But they won’t be substrates for just any enzyme. Each enzyme only works on certain chemical substrates. Like receptors, enzymes are picky about what fits into their active sites. Just as some keyholes accept more than one type of key, some enzymes are more picky, or specific, than others.
A substrate clinging to an enzyme’s active site may feel its parts tugged one way or the other, because of electrostatic forces, and this can break pieces off the substrate, turning it into something new. Sometimes an enzyme introduces their substrates to other chemicals that they are also hanging on to, and two newly introduced chemicals bond together, again, forming something new. Enzymes both break down large chemicals into smaller ones, and join smaller ones to make bigger ones. Sometimes they just rearrange the parts on one chemical, unhooking parts and rejoining them in different ways to make a new, rearranged thing.
Enzymes are responsible for most of your body’s alteration of chemicals.
Many people think of enzymes as simply things that aid digestion, breaking large food chemicals into smaller, more digestible ones. But you should not underestimate all that enzymes do in your body. Enzymes do a whole lot more than help you digest your dinner. They carry out most of your body’s chemical transformations.
Some enzyme-affecting herbs make headaches and fevers go away. Others prevent blood clots. A few herbs act like the popular prescription statin drugs, hindering an enzyme that makes cholesterol. Some inhibit bacterial enzymes from chewing their way into your tissues. Others stimulate liver cells enzymes to make protein and regenerate. And a few herbs, in excess, can inhibit nerve-associated enzymes, to paralyze your muscles kill you. So, herbs that influence enzymes can do a whole lot more than modulate your digestion.
Some herbal chemicals must first get changed by your enzymes in order to work.
Herbal chemicals frequently get altered by enzymes, and this alters their functions. Sometimes an herbal chemical requires an enzyme to turn them into a working product. For example, many herbs contain glycosides, chemicals that have sugars bonded to them. Some glycosides just don’t work unless your gut’s bacterial enzymes (glycosidases), remove their sugar appendages to release the effective, sugar-free chemical. For example, sennosides are glycosides from the herb senna, and are now quite popular in over-the-counter laxatives. But sennosides don’t work as laxatives as well as their sugar-free versions, so you have to count on your intestinal enzymes to chop off the sugar to activate them.
Other herbal chemicals are disabled by your enzymes.
Other herbal chemicals suffer disablement after enzymatic tinkering. The active ingredients from papaya and pineapple aid digestion, because they are actually enzymes that help break down your food. However, they don’t last long, as they are quickly broken down into less useful forms by your own digestive enzymes.
Herbal chemicals often work by inhibiting the action of one of your enzymes.
Herbs frequently work by hindering enzymes. Herbal chemicals can do this by sitting inside an enzyme’s active site, but they remain unaffected by enzyme’s business end. Like a wrench inside the machine, the chemical blocks the enzyme from working on its substrate. This type of interaction is called competitive inhibition. On the other hand, sometimes an herb will bind outside an enzyme’s active site, and though it doesn’t block the business end, it can still hamper the enzyme. For example, if you are operating a drill, with big, clunky gloves on its hard to operate it, even though there’s nothing blocking the drill bit. This type of interaction is called noncompetitive inhibition.Sometimes herbal molecules affect an enzyme in a roundabout way without even touching it. They get another molecule to do the job. In some cases, an herbal molecule can even make an enzyme more active.
Some of the best-known herb-enzyme interactions are COX inhibition.
Many herbs possess chemicals that inhibit the cyclooxygenase enzyme, called “COX,” for short. There are different versions of the COX enzyme, and differnt herbs vary by which kind they mess with. But inhibiting COX enzymes is just what aspirin does, so you can expect these herbs act like aspirin. In fact, you can thank herbal medicine for aspirin.
As early as the fifth century B.C., the Greek Hippocrates asked his patients to chew willow bark to reduce their pain and fever. It might have had some success, because willow bark remains popular in herbal medicine to this day. Willow bark was the original source for salicylic acid, which was synthetically modified to become aspirin, acetylsalicylic acid, in the late 1800’s, which is less irritating than the herbal chemical. Your body actually converts some aspirin back into the original herbal chemical, salicylic acid, using an enzyme (esterase enzymes). Both aspirin and the herbal salicylic acid inhibit COX.
That aspirin was made from willow bark may explain why willow is the most touted producer of aspirin-like chemicals collectively called salicylates. The other most commonly noted salicylate containing herbs are birch bark and wintergreen. But salicylates are abundant in the plant kingdom. Most herbs, including these, have salicylate concentrations too low to represent a regular aspirin pill, unless you drink an inordinate amount of their tea. On the other hand, these herbs’ oils, like wintergreen oil—its distinctive skin-soluble ingredient provides the characteristic minty smell of some pain-relieving muscle rubs—have salicylate concentrations that are so high that if you drank it, you would experience a crisis very similar to aspirin overdose. But hindering the COX enzyme in a more limited way seems beneficial, and both aspirin and herbal salicylates do it.
Why is the COX enzyme so nasty? Not all forms of the COX enzyme are bad, but some COX enzymes (“COX-2 enzymes”) are better at creating pain-enhancing, inflammatory chemicals. Herbs that block COX hamper their creation, preventing pain and inflammation. Other versions of the COX enzyme (“COX-1 enzymes”) make more beneficial prostaglandins, which protect your stomach from its own acid, however. Not surprisingly, these herbs, like aspirin, can upset your stomach.
If you can stomach them, COX inhibitors seem to be a good deal, because they apparently hinder the production of inflammatory chemicals that might ultimately lead to cancer. Also, COX enzymes can create chemicals that make your blood clot, which is good if you are bleeding but bad if the clot lodges in your heart or brain’s blood vessels, creating a heart attack or stroke. Trace amounts of salicylates found in plants may, in part, explain why consuming lots of fruits and vegetables protects you from stroke, cancer, and heart disease, as does aspirin. Some health writers are even effusively calling plant salicylates “vitamin S”, which sounds a tad exalted, but gets our collective mothers’ point across: eating more fruits and vegetables is good for you.
Some herbal chemicals induce of one of your enzymes, causing you to make more of that enzyme.
Some herbal chemicals cause more of one of your enzymes to be made, and that enzyme is then said to have been induced by the herbal chemical. If you have more machines that do a particular job, that job will be done more often. And if you induce an enzyme, you make more of it, and you can be sure that enzyme’s job will be accomplished more frequently.
St. John’s wort, an herb used for depression, induces production of a liver enzyme that prematurely degrades oral contraceptives. It is not yet clear if St. John’s wort relieves depression, but it does upgrade production of this enzyme. So, if you are a woman taking birth control pills, you should be aware that St. John’s wort could subvert your contraceptive efforts.
More favorably, many herbs induce manufacture of detoxifying enzymes, that is, enzymes that have a knack for converting bad-for-you molecules into more benign ones. Ellagic acid, found in high concentrations in strawberries, grape skins, and grape seeds, causes more production of the detoxifying enzyme glutathione S-transferase. Some of garlic’s stinkier components induce this enzyme, too, as well as other toxin-disarming enzymes, glutathione peroxidase and quinone reductase. All these enzymes are immediately recognized by biochemists for their power to disable damaging and carcinogenic molecules.
A lot of plants induce your helpful enzymes, yet another good reason to eat your fruits and vegetables. But how do plants do this? In some cases, plants’ trace amounts of toxic secondary metabolites induces your cells’ defensive enzymes. So, you may find it paradoxical to thank plants for containing small amounts of toxins, because these toxins stimulate production of your detoxifying enzymes.
The Bottom Line
Enzymes are proteins that, like little machines, change one chemical into a different one, and they remain unchanged, themselves. Each type of enzyme performs a different sort of chemical transformation. Like a lock accepting a key, an enzyme only accept certain things to work on, which are called its substrates. Some herbal chemicals must get changed by your enzymes in order to work. Other herbal chemicals are inactivated by your enzymes. Many herbal chemicals work by inhibiting one of your enzymes. Herbal chemicals often induce one of your enzymes. This means that the production of that enzyme is enhanced, and that enzyme will be more active.
Your pet has different receptors and enzymes
If you have a pet, you may have noticed that more and more vets are advertising that they can provide your pet alternative, herbal treatments. If you love your pet, you should be aware that animals have different enzymes and receptors than humans do, so they will they respond differently to herbal medicine. A helpful, harmless herb for you might do real damage to your pet. Not all herbs for pets are bad, but you can’t assume that something that is good for you is good for your pet. If you have a dog, for example, be sure that the herb you are interested in giving him was tested in dogs, and its effect is well-known in dogs, rather than in some other species. You can ask your vet if they are aware of such studies on your species of pet. Some vets are really up-to-date on this subject, but others are just “going with the flow”, so you might want a second opinion.
Herbal treatments traditionally used by humans are now enthusiastically recommended for your animal companions, without much forethought. Several “natural” pet food lines even include herbs. But animal receptors and enzymes are not always shaped like yours, and they do not respond in the same way to the same herbs. Sometimes one animal species possesses a receptor that another species lacks. For example, you can only look upon your catnip-intoxicated cat with amusement and perhaps envy, because you do not have the receptor that binds catnip’s active ingredient. Disparities in our receptors and enzymes means that animal research will always provide us with an inexact estimate of how a chemical behaves in humans. So, that is why you should use this same philosophy, giving more credibility to human studies to animal ones, on an herb when treating yourself. Though many human studies of herbs are scant, they are growing in number. Doctors are realizing that herbs can help or hinder their patient’s treatment.
Garlic’s inclusion in several lines of pet food has recently sparked a lot of unresolved debate. Garlic’s best-documented effect on humans is its blood-thinning effect, because it inhibits an enzyme that causes your blood platelets to stick together into a clot. But garlic and the related onion do strange things to cats’ and dogs’ blood cells, if the animal eats enough of these plants. It causes a type of anemia that can even kill the animal. The pet food companies claim their garlic ingredient is present in such small amounts that it does no harm, and still provides benefits. This could be true, but the point is debatable, so some people buy garlic-free versions.
I mentioned above how chocolate, coffee, and tea are plants that block your adenosine receptor, preventing adenosine from making you sleepy. Blocking your adenosine receptor in this way is relatively harmless to you, but can be toxic for cats, dogs, rodents, and even birds. While the theobromine in these plants makes us feel pleasantly awake, it can cause animals vomiting, seizures, coma, and death. Unless valid research indicates that an herb is safe for your species of pet, you should be wary gambling your pet’s health on it.
The Bottom Line
Herbal medicine for pets has exploded in popularity, but pets have different receptors and enzymes than you do, so will respond differently to the same herbs. If you really want to give your pet herbs, talk to a vet who is well versed in studies of that herb in your species of pet.