XENOBIOTIC: METABOLISM, DIETARY SOURCES, METABOLISM, TRIGGERED RESPONSES - BIOLOGY - 2025

The xenobiotics are foreign chemical substances to the human body, including drugs, food additives, contaminants, chemical carcinogens and many substances that enter the body by different routes from the environment.

The word "xenobiotic" derives from the Greek word "xenos" which means foreigner and "bios" which means life. These foreign compounds, or that normally are not part of the chemical compounds that make up the human body, can be of natural or synthetic origin.

Liver metabolism of xenobiotic drugs (Source: Drriad / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)

Most xenobiotics are metabolized by the body in order to be eliminated, however, there are some that cannot be eliminated or whose elimination process is very slow, so they accumulate in the body and can cause damage or toxicity.

More than 200,000 environmental chemicals are known to be identified as xenobiotic substances, most of which can be metabolized, that is, transformed, in order to be eliminated. These transformations occur mainly in the liver. However, some xenobiotics can be excreted or eliminated unchanged.

Several factors can affect the metabolism of xenobiotics. These include age, sex, certain genetic factors and some enzyme inductions caused by certain xenobiotics.

When the xenobiotic is a drug, its metabolism may involve its activation or it may decrease or end its action. The toxicity of some xenobiotics can be verified in several ways; for example, cyanide is very toxic at very low concentrations, as it blocks the respiratory chain; others are cytotoxic as they bind covalently to DNA, RNA, or proteins.

Some xenobiotics can trigger antigenic reactions, they can be carcinogenic, or they can even be completely harmless (non-toxic).

Xenobiotics metabolism

Humans are constantly exposed to a wide variety of xenobiotic substances. These include drugs, toxic agents, mutagens, and carcinogens. Many of these substances enter the body when they are ingested with food in the diet.

Xenobiotic compounds can react with intracellular macromolecules such as DNA (or directly with cellular structures) causing damage and / or injury. To counteract these harmful effects, the body has two defense systems: detoxification enzymes and antioxidant systems.

Xenobiotic metabolism (Source: TimVickers / Public domain, via Wikimedia Commons)

The metabolism of xenobiotics can be grouped into two processes or phases. The first has hydroxylation as its main reaction and the second includes the conjugation of the hydroxylated products. These processes take place mainly in the liver, although some initial reactions can occur in the epithelial barrier of the skin and in other tissues such as the lungs.

The hydroxylation phase is catalyzed by a series of enzymes of the class of monooxidases or cytochromes P450. In addition to hydroxylation, these enzymes participate in deamination, dehalogenation, desulfurization, epoxidation, peroxidation and reduction processes.

The enzymes of the cytochrome P450 family are aldehyde oxidases, xanthine oxidases and peroxidases. In this first phase, some esterases and enzymes other than cytochrome P450 participate in some hydrolysis reactions.

In the second phase, some polar products are produced as a result of the conjugation which, being soluble in water, are easily excreted. Conjugation is produced by the effect of specific enzymes that bind the hydroxylated product with different molecules, among which are: glucuronic acid, sulfate, acetate, glutathione, amino acids or methyl groups.

Dietary Source of Toxic and Carcinogenic Xenobiotics

The dietary source of carcinogenic substances includes compounds that are produced when fat, meat or protein is cooked or when some natural products derived from certain plants such as alkaloids and some by-products of mold are ingested.

Among these substances, the most studied for their carcinogenic effects are those generated by overcooking meats, such as polycyclic aromatic hydrocarbons and heterocyclic aromatic amines.

Other xenobiotics that people ingest throughout their lives are industrial and environmental pollutants such as diesel engine exhaust, as well as pesticides that end up contaminating water and food. Some medications are also included, both those that are prescribed and those that are over the counter.

Nitrates used to preserve meat and fish can pollute soils and waters; these are related to glandular carcinomas in animals.

Factors affecting the metabolism of xenobiotics

Many factors can affect the activity of the enzymes that metabolize xenobiotic substances. Their activity differs greatly between species, so the toxic or carcinogenic effect of a xenobiotic cannot be freely transpolated from one species to another.

Significant differences have been reported between individuals regarding the activity of the enzymes responsible for the metabolism of xenobiotics. These differences often depend on genetic factors, the age and sex of the individual in question.

The simultaneous consumption of several xenobiotic substances can generate enzymatic induction. The metabolites generated during the metabolism of some xenobiotics can inhibit or stimulate the activity of detoxifying enzymes.

This effect is very important when evaluating the response to certain drugs, since the combination may require dose adjustments.

Responses triggered by xenobiotics

When the xenobiotic is a drug, the hydroxylation reactions of the first phase of metabolism can cause the activation of the drug or, on the contrary, if it was already active, then it will be metabolized to an inactive polar form and then eliminated.

There are some adverse reactions induced by certain drugs that depend on the differences of genetic origin that exist between different individuals in terms of the structure of various enzymes and proteins.

Free radical toxicity (triggered by xenobiotics) (Source: Dan Cojocari / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0) via Wikimedia Commons)

Thus, some collateral effects that only appear in a very small percentage of individuals are described, such as hemolytic anemias, malignant hyperthermia, altered nicotine metabolism that protects against tobacco dependence, etc.

The toxic effects of xenobiotics may depend on the dose or the substance ingested. Some xenobiotics such as certain poisons are toxic with very low doses, others are metabolized very slowly and when their consumption is continuous they accumulate until the toxic effects are generated with higher doses.

Xenobiotic substances can cause a wide variety of biological effects. These include beneficial pharmacological responses in the treatment of many diseases, toxic reactions, immunological reactions, and carcinomatous effects that can end up generating cancer in various organs and tissues.

References

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