Toxification involves the production of toxic substances during metabolism in the organism. It can occur when foreign substances (xenobiotics) are broken down in the body. When prodrugs are used, a mild and intentional form of toxicity occurs.
What is toxicity?
All substances in the organism undergo biotransformation in the liver after ingestion. The goal of this substance transformation is to detoxify the body. Detoxification or toxification characterizes a process in the organism, which transforms ineffective or weakly toxic foreign substances into biologically effective or even highly toxic substances within the framework of metabolism. Normally, foreign substances absorbed from the outside, which either have no significance for the body or can cause harmful effects, are transformed in the liver into ineffective and readily water-soluble compounds so that they can be excreted via the kidneys, sweat or breath. This is intended to detoxify the body. However, the enzymes act non-specifically. Thus, it can happen that certain ineffective substances become effective or even toxic on the contrary. In some cases, this is explicitly intended. For example, some drugs only develop their efficacy through biotransformation in the body. However, highly toxic substances can also be produced that are harmful to the organism. Each person is equipped with individual enzymes, so that toxification or the development of a drug’s efficacy does not occur to the same extent everywhere. This is one of the reasons for the occurrence of different side effects of drugs.
Function and task
Toxification of xenobiotics is usually problematic for the body. However, in the case of drugs known as prodrugs, this change is intentional. These substances form effective metabolites only during detoxification in the liver. This applies, among others, to the drugs codeine, clopidogrel, levodopa, metamizole, phenacetin or omeprazole. For example, codeine is converted into morphine or phenacetin into paracetamol. Levodopa is considered a precursor of epinephrine, norepinephrine or dopamine for the treatment of Parkinson’s disease. Even the thyroid drug carbimazole or the sleeping pill chlordiazepoxide only become effective substances through biotransformation in the body. Regardless of their chemical structure, all substances in the organism undergo biotransformation in the liver after ingestion. The aim of this substance transformation is to detoxify the body. The substances are converted into a water-soluble form so that they can be quickly removed from the body. In the first phase, unspecific reactions take place that apply equally to all foreign substances. Oxidation, reduction and hydrolysis reactions occur. In the process, all compounds acquire specific functional groups. In some cases, existing functional groups are altered. These reactions are catalyzed by the enzymes of the cytochrome P-450 system. In a second phase, conjugation reactions take place. In this process, the metabolites of the foreign substances are linked to endogenous water-soluble substances via the functional groups. Thus conjugation reactions occur with glucuronic acid, acyl and acetyl residues, amino acids, methyl groups, glutathione or also sulfates. In this form, the metabolites are transportable. In the third phase, they are now transported out of the cells via transport molecules and then transported through the body to the kidneys by the bloodstream and lymphatic system. The conversion of ineffective substances into effective or even toxic compounds can happen during their first passage through the liver as part of the so-called first-pass effect. In a first-pass effect, the ineffective substances travel through the liver via the enterohepatic circulation, where they are biochemically converted into an effective substance.
Diseases and disorders
However, toxification or poisoning often results in the formation of sometimes extremely toxic substances from ineffective compounds. For example, aldehydes and carboxylic acids are formed during the metabolization of alcohols in the first phase. As a rule, this is not a problem, since the resulting compounds are usually nontoxic. Methanol is also primarily non-toxic, but its metabolization produces the toxic formaldehyde as an aldehyde and the corrosive formic acid as a carboxylic acid. Both substances are far more toxic than methanol. Methanol consumption can thus lead to blindness or even death.Toxification can also occur if the starting substances are used in too high doses. Due to the increased enzyme activation, many activated metabolites are formed in the first phase, which cannot be inactivated so quickly because the capacities for the second phase are not sufficient. The activated metabolites then act as free radicals and damage the cell as well as the genetic material. During cell damage, lysosomal enzymes are released, which can completely destroy the cells. Especially liver and kidneys are damaged. An example of this effect is taking a high dose of paracetamol. Paracetamol poisoning can lead to death by liver decomposition. Partly, toxification can also start in the second phase of metabolization. This can occur in renal insufficiency. For example, although the morphine metabolite morphine-6-glucuronide is usually cleared rapidly from the kidney, it has been found that in renal impairment, further conversion occurs, making the metabolite even more potent than the parent drug. However, phase 2 toxification is very rare. Another example of toxification is ragwort poisoning. The parent compounds in ragwort are pyrrolizidine alkaloids (PAs), which are not toxic themselves. If contact with the alkaloid is not very intense, it is well broken down in the body. However, if the body has been exposed to high amounts, the intermediate metabolites cannot be broken down quickly enough. They then attack liver cells and genetic material.