Medicine and Poison

"poison"What comes to mind when you hear that word? Poisonous snakes, poisonous mushrooms, pufferfish, aconite, arsenic compounds... As you can see, there are many poisons all around us.

Humans have a very long history of dealing with poison.

Obtaining and consuming food is a fundamental necessity for survival. Therefore, distinguishing between non-toxic and poisonous substances and recording their contents has been a crucial matter of life and death since ancient times. In fact, it is known that descriptions of poisons can be found on papyrus used for record-keeping in ancient Egypt and on clay tablets written in cuneiform script during the Mesopotamian civilization.

How do the many poisons lurking around us affect our bodies?

When we think of poisons, we might imagine something like snake venom that rapidly damages our health. However, there are also chemical substances that slowly and gradually erode our bodies over a long period of time and can be carcinogenic. With such substances, it is often difficult to notice any changes in one's health until it is too late, and by the time symptoms appear, treatment may be difficult. For these chemical substances as well, it is important to thoroughly investigate their toxicity beforehand and take steps to prevent harm.

The strongest poison

How exactly is the strength of a poison quantified? For poisons that cause immediate death after ingestion, the LD50 value is used as a guideline. LD50 stands for Lethal Dose 50%. In other words, it's the amount of a substance that, if administered, is expected to kill half of the animals that receive it. For example, suppose a substance has an LD50 of 10 mg/kg. If 600 mg of this substance is administered to a person weighing 60 kg, there is a 50% chance of death.

Of course, since toxicity tests cannot be conducted on humans, please keep in mind that the values ​​are estimated from LD50 calculated from experiments using animals such as mice and rats.

The most potent toxin currently known is botulinum toxin, produced by the bacterium Clostridium botulinum. It is said that one gram of botulinum toxin could potentially kill approximately 55 million adults.

Clostridium botulinum lives in the soil, and if food is not properly sterilized, food poisoning caused by botulism can occur.

Botulinum toxin is a neurotoxin that paralyzes the nerves that control muscle movement. As a result, food poisoning caused by botulinum toxin can lead to paralysis of the limbs, and in severe cases, respiratory distress and death.

Arsenic compounds

One of the most potent toxins is arsenite, a compound containing arsenic. Arsenic has chemical properties similar to phosphorus, a constituent element of DNA (deoxyribonucleic acid) and cell membranes. Therefore, when arsenite enters the body, phosphorus is replaced by arsenic, disrupting normal metabolic activity. Ingesting a large amount of arsenite in a short period of time can cause vomiting, diarrhea, and death.

Arsenic trioxide has been involved in tragic incidents such as the Morinaga arsenic milk poisoning incident in 1955 (over 130 deaths) and the Wakayama poisoned curry incident in 1998 (4 deaths). However, arsenic trioxide is also used as a treatment for relapses of intractable acute promyelocytic leukemia. It truly is a case of "the line between poison and medicine is very thin."

Intercellular communication

Why can poison be used as medicine? To understand this, let's first take a closer look at the differences between a "healthy body" and a "sick body."

The human body functions as a single entity, comprised of various organs such as the liver, kidneys, and brain. These organs are made up of numerous cells, which communicate with each other using proteins such as enzymes, ion channels, and various receptors, ensuring orderly function. This proper communication allows the body to operate normally.

Let's take the heart as an example. The heart pumps blood throughout the body by beating continuously 24 hours a day without rest. For the heart to pump blood, the myocardial cells that make up the heart need to contract in an orderly manner, not randomly. For this reason, the heart has "pacemaker cells," and these pacemaker cells send electrical impulses to the entire heart, creating a rhythm of contraction.

Electrical stimuli are transmitted through a protein called a sodium channel located in the cell membrane of cardiomyocytes. This protein plays a role in allowing only sodium ions to pass from outside the cell into the cell. When sodium channels open and sodium ions flow into the cell, the potential difference (voltage) between the inside and outside of the cell changes. This change in voltage activates the cardiomyocyte, causing it to contract.

However, when information is not transmitted properly between cells, health problems can arise. "Arrhythmia" is one example of this. Arrhythmia is a condition in which the heart does not beat at a consistent rhythm, making it impossible to circulate blood properly.

Poison and medicine are the same thing.

A drug called "lidocaine" is widely used to treat this arrhythmia. Lidocaine works by inhibiting the function of sodium channels.

The cause of arrhythmia is that abnormalities in pacemaker cells or other factors prevent the contraction signals from being properly transmitted to cardiomyocytes, leading to abnormal activation of the cardiomyocytes. Lidocaine inhibits the function of sodium channels, suppressing this abnormal activation and consequently reducing arrhythmia.

On the other hand, there is tetrodotoxin, which is famous as the toxin found in pufferfish. This tetrodotoxin, like lidocaine, actually inhibits the function of sodium channels. And that is precisely what makes pufferfish poison so toxic. When tetrodotoxin enters the body and inhibits sodium channels throughout the body, the heart muscle and respiratory muscles become unable to contract. As a result, respiratory paralysis and heart failure occur, leading to death. This is the mechanism by which pufferfish poison produces toxicity.

Thus, both drugs and poisons, when examined in terms of their behavior within the body, share the common property of acting only on specific proteins while not affecting other proteins. This property is called "selectivity."

Substances that have some kind of effect on living things, including humans, are called "bioactive substances." The distinction between a medicine and a poison simply depends on whether the bioactive substance is beneficial to humans or not. It's impossible to neatly categorize a substance as either a poison or a medicine.

side effect

The fact that poison can be used as medicine implies, conversely, that medicine can also be poison. Undesirable drug effects, or "side effects," can be considered the effects of the "poison" that the drug produces. Why do side effects occur? The causes can be broadly divided into two categories: "concentration" and "selectivity."

Let's start by looking at side effects caused by "concentration." These are side effects that occur when taking a large amount of medication at once.

Let's consider "diabetes." Diabetes is a disease characterized by persistently high blood sugar levels. If diabetes persists for a long time, it can lead to nerve damage, kidney failure, blindness, and other complications. "Insulin" is used to treat diabetes. Insulin is a hormone secreted by the pancreas that lowers blood sugar levels. By administering insulin, blood sugar levels can be lowered to normal levels.

However, if insulin is administered by mistake in large quantities, blood sugar levels will drop too low. Hypoglycemia can cause impaired consciousness, and in severe cases, it can lead to coma and death.

Thus, taking a drug beyond its effective concentration can cause its main effects to become too strong, potentially resulting in it exhibiting toxic properties.

Just as poisons have an LD50 (Low Liverpool Value), drugs have a defined median effective dose (ED50). ED50 is the dose at which a drug is effective in 50% of those administered it. Increasing the drug concentration further leads to side effects. The dose at which toxicity occurs in 50% of administered animals is called the median toxic dose (TD50). At even higher concentrations, it can be fatal.

A large difference between ED50 and TD50 values ​​indicates that the drug is less likely to cause side effects from overdose, while a small difference indicates that the drug requires careful attention to dosage. A small difference means that even a slight mistake in dosage can lead to side effects that outweigh the drug's effects, and in serious cases, can be fatal.

The second cause of side effects is "selectivity." Just as sodium channels allow only sodium ions to pass through, proteins have a mechanism to recognize only specific targets. This can be likened to the relationship between a lock and a key.

Proteins are like keyholes. Only substances that fit into these keyholes can react with that protein. If other substances try to attach to a protein, the reaction will not proceed because their shapes do not match.

However, this selectivity is not as perfect as a real lock and key. It is believed that there are as many as 100,000 different types of proteins in the human body. With so many proteins, it is extremely difficult to create a substance that binds to only one type, and it inevitably binds to other proteins.

Many people have likely experienced stomach upset as a side effect when taking aspirin, a pain reliever. This side effect is also related to "selectivity."

Aspirin works by inhibiting the activity of an enzyme called "cyclooxygenase (COX)," thereby reducing inflammation and providing pain relief. There are mainly two types of COX, COX-1 and COX-2, each with different functions. COX-1 is involved in regulating the function of the stomach and kidneys, while COX-2 is involved in inflammation.

To suppress inflammation, it would suffice to inhibit only the function of COX-2, but aspirin inhibits not only COX-2 but also COX-1. As a result, the protective function of COX-1 on the gastric mucosa is suppressed, leading to stomach irritation. Currently, development is underway for drugs that selectively inhibit COX-2.

Regarding drug side effects, Dr. Kanno explains: "Previous research suggests that a single drug acts on an average of 5 to 6 signaling pathways. This means that, in addition to the desired effects, some undesirable signaling may occur in several places, potentially resulting in side effects in the body. Currently, research is progressing to comprehensively analyze signaling pathways within the body to understand the pathways through which toxicity and drug efficacy manifest. Applying this research could lead to the development of drugs with fewer side effects."

Poison is the excellent "seed" of medicine.

As we have seen, poison and medicine can be said to be two sides of the same coin. Therefore, poison can also be used as a "seed" for medicine. Currently, research is being conducted to create new medicines from poisons. Let me introduce the latest research being conducted by a French research group.

In Africa, there is a venomous snake called the "black mamba." This snake possesses an extremely potent neurotoxin, so deadly that a single bite can be fatal to an adult. This neurotoxin inhibits the signals that control muscle contraction and relaxation. As a result, it causes paralysis of the limbs and difficulty breathing. The body becomes numb in less than 10 minutes after being bitten, and in some cases, it can be fatal. It is the fastest-acting snake venom.

However, a closer analysis of the venom of this snake revealed a substance with analgesic properties. The research group named this substance "manbalzin."

Currently, morphine, a narcotic, is used to relieve pain in terminally ill cancer patients. Mambalzin has a similar level of analgesic effect to morphine. Moreover, it has fewer side effects such as nausea and respiratory depression, as well as a lower risk of addiction compared to morphine.

Further research is needed before this analgesic component can be developed into a drug for clinical use. However, it is expected to lead to the design of entirely new analgesics that are different from existing medications.

Thus, there is a high possibility that animal and plant toxins could lead to the development of important pharmaceuticals. It is likely that the development of new drugs from toxins will continue in the future.