Toxicity of Metabolites

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Many substances known to be poisonous are not directly harmful to the body but can become toxic after being metabolized in the liver.

When foreign substances enter the body and are absorbed into the bloodstream, the liver is responsible for breaking down the chemical substances into metabolites, which can be excreted via the renal system. However, when some substances are metabolized, the resulting metabolites are toxic to the body and can cause fatal results.

Image Credit: E. M. Lara / Shutterstock
Image Credit: E. M. Lara / Shutterstock


A prime example of a poison that exerts its effect by way of a metabolite is methanol, also commonly known as wood alcohol.

When methanol is consumed and absorbed into the bloodstream of a mammal, it passes through the liver, which oxidizes it into formaldehyde and formic acid. The effect of the metabolite formic acid is likely to cause the metabolic acidosis response observed when humans consumed methanol.

Acetaminophen (Paracetamol)

Another example of toxic metabolites comes in the commonly used pain relief and antipyretic medication acetaminophen, also known as paracetamol, which is extensively metabolized in the liver.

When a standard dose of acetaminophen is taken, it is normally metabolized in the liver primarily by processes of glucuronidation and sulfation. When high doses are taken, the glucuronidation and sulfation pathways become saturated and metabolism relies more on other pathways such as P450-dependent glutathione conjugation. However, glutathione cannot regenerate as quickly as glucuronic acid and sulfate, leading to toxicity in the liver, particularly for chronic users of acetaminophen with high doses.

Genetic Variability of Liver Enzymes

There are many different enzymes in the liver, each playing a different role in the metabolism of different substances.

The availability of enzymes in the liver can vary greatly between individuals, and, as a result, the efficacy of metabolism of different substances is not equal. For example, a person with a greater concentration than the average of a particular enzyme needed to metabolize a substance into a toxic metabolite will likely be more affected because it is produced more rapidly. Conversely, someone who has less of the enzyme needed in the metabolism process will likely be less affected by the toxic metabolite.

Genetics plays a large role in the presence and quantity of different liver enzymes. Some family lines have particularly low or high levels of specific enzymes and have a different response to substances and their metabolites as a result.

Pharmaceutical Activity of Metabolites

The metabolism of chemical substances does not always lead to toxicity, and, in some cases, metabolites can be used to our advantage in the medical field.

Codeine is a medication used for pain relief, although it has little effect on the pain pathways in the human body because its metabolites are responsible for the analgesic effect.

When codeine passes by the liver, it is metabolized to norcodeine, codeine-6-glucuronide, and morphine. The metabolite morphine is the most important in the medication's pain-relieving effect, which occurs by way of the enzyme CYP2D6.

This enzyme is known to vary greatly among different individuals, which accounts for the varying results. Some patients notice large effects with small doses because they are extensive metabolizers with more CYP2D6 in their liver, whilst others barely notice the effect even with large doses.


Further Reading

Last Updated: Apr 6, 2021

Yolanda Smith

Written by

Yolanda Smith

Yolanda graduated with a Bachelor of Pharmacy at the University of South Australia and has experience working in both Australia and Italy. She is passionate about how medicine, diet and lifestyle affect our health and enjoys helping people understand this. In her spare time she loves to explore the world and learn about new cultures and languages.


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  1. Jennifer Torola Jennifer Torola United States says:

    Hello!  You stated, "For example, a person with a greater concentration than the average of a particular enzyme needed to metabolize a substance into a toxic metabolite will likely be more affected because it is produced more rapidly." Is there a way for me to be tested for the enzyme?  Could having this enzyme lead to Pure Red Cell Aplasia after using something with Permethrin or Polyethylene glycol?

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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