Biotransformation

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The biotransformation is a process in the metabolism of living organisms, in which not be excreted substances transformed by chemical processes that can be excreted substances (transformed) are.

During the physiological metabolism of the body, substances repeatedly accumulate that cannot be excreted directly in the urine or stool . Most of these substances ( bile pigments , steroid hormones) are lipophilic , i. H. hardly or not at all soluble in water. In addition, the organism absorbs foreign substances from nature with food ( xenobiotics ), or substances synthesized by humans (mainly medicines , drugs , preservatives , pesticides, etc.)

An accumulation of these substances in the body would be fatal. In order to convert these substances into an excretable form, many tissues, especially the liver , are capable of biotransformation. The ability to do this, however, decreases in old age (reduced liver size and reduced enzyme activity).

The biotransformation can be divided into two phases (phase I and phase II). Phase I (conversion reactions) add functional groups (-OH; -SH) to the non-polar molecules. In phase II (conjugation reactions) the molecules are linked (conjugated) to water-soluble molecules via the functional groups and can then be excreted either via the kidneys or via the bile.

It should be noted that the organism does not specifically “recognize” toxic or biologically active substances and converts them into substances that are non-toxic or inactive for the organism. Rather, the process of biotransformation is largely based on enzymes that have a relatively low substrate specificity, that is, they catalyze reactions in a whole group of substances. This generally leads to a detoxification of the organism or to an inactivation of chemical substances; However, the reverse process can also take place, i.e. a substance that is non-toxic to the body is converted into a toxic substance by biotransformation (poisoning) or molecules that are not biologically active are converted into biologically active molecules (activation). Medicines are sometimes administered in the inactive form and only converted into the active form through biotransformation in the body, including the anti- thyroid drug carbimazole or the sleeping pill chlordiazepoxide . The initial form is called the parent substance, the resulting biotransformation products are the metabolites .

Phase I reactions (functionalization reactions)

In this reaction step, functional groups are inserted into substances or existing functional groups are changed. The reactions are catalyzed by enzymes , the majority of which have a relatively low substance specificity, i.e. act on a whole group of chemical substances. The following are typical reactions and the enzymes responsible for them (name ending: -ase):

Oxidation reactions

Reduction reactions

Hydrolysis reactions

Phase II reactions (conjugation reactions)

In the second phase, the foreign substances or metabolites (intermediate products) of the first phase are combined with endogenous (i.e. the organism's own), mostly highly water-soluble substances. As a result, on the one hand, the water solubility of intermediate products of the first phase is (mostly) greatly increased. On the other hand, potentially toxic reaction products from the first step can be further detoxified and finally excreted. In humans and other vertebrates, excretion then takes place e.g. B. via the kidneys , sweat or breathing. The reaction products of the 2nd step are also known as conjugates. Conjugates do not have to be excreted directly, but can be further metabolized beforehand. If suitable binding sites already exist, phase II reactions can also take place directly and without preceding phase I reactions. Phase II reactions can also be omitted in some cases.

Conjugation with glucuronic acid

The starting product for this reaction is UDP- glucuronic acid . With the help of a glucuronyl transferase , the glucuronic acid can be transferred to various functional groups:

  • OH group → O-glucuronide
  • NH group → N-glucuronide
  • SH group → S-glucuronide
  • COOH group → Ester-Glucuronide

These reactions are used to conjugate steroids , bilirubin, and phenolic rings .

Conjugation with sulfuric acid or sulfate [SO 4 ] 2−

When cysteine is broken down , sulfuric acid is formed , which is then converted into 3'-phosphoadenosine-5'-phosphosulfate with ATP in several steps . With the help of a sulfotransferase (phenol sulfotransferase or hydroxysteroid sulfotransferase) the sulphate group can be transferred to different groups. The substrates for the two enzymes are mainly steroid hormones , which can then be excreted renally.

Conjugation with acyl or acetyl residues

In this reaction, aromatic and aliphatic amines are acetylated with the aid of acyl and acetyl residues. This mainly serves to break down sulfonamides (antibiotics), caffeine , hydralazine and isoniazid.

Conjugation with amino acids

A foreign acid is first activated with S-CoA and then transferred to an amino acid (e.g. glycine is bound to aromatic acids ).

Conjugation with a methyl group

Substrates such as catecholamines , phenols or thiols are methylated with the help of methyltransferases and SAM ( S-adenosylmethionine ), i. that is, methyl groups are transferred to these substrates.

Conjugation with glutathione

The glutathione S-transferase is the central enzyme in the conjugation. During this process, the SH group of glutathione is first linked with an aromatic or halogenated compound. The glycyl and glutamyl radicals are then split off and the amino nitrogen of the remaining cysteinyl radical is conjugated with acetyl-CoA.

The conjugates are usually further metabolized to mercapturic acids .

Phase III reactions (transport)

Phase III reactions include transport processes via the bloodstream , the lymphatic system and transport proteins , some of which are not metabolized. Phase III reactions also include various reactions such as the breakdown of GSSG / GSH to N- acetylcysteine , cysteine and glutamate by means of γ-GT and dipeptidases . The membrane is transported by special carriers, such as the multidrug resistance-related proteins from the group of ABC transporters .

Prodrugs and toxification

Some substances are absorbed in a non-active form. They are only transferred into the actual active form through the conversion through biotransformation. Is it a drug, such as B. the sleeping pill chlordiazepoxide , these drugs are called prodrugs. If the supplied substance is converted into a toxic metabolite through biotransformation , this process is called poisoning . The best example of this is methanol , which on its own is non-toxic, but is converted into the toxic formaldehyde and later into formic acid during the breakdown process. Similar to the prodrugs, morphine is converted into morphine-6-glucuronide by glucuronidation in the liver, which has a much stronger effect than morphine itself. Such conversion and activation effects can be achieved by the first passage of a substance through the liver; they are then also referred to as first-pass effects .

Cytochrome P450 Oxigenases

These microsomal enzymes (located in the smooth endoplasmic reticulum), abbreviated as CYP 450 , are of particular importance in biotransformation. Your task in the phase I reaction is to convert molecular oxygen into a reactive form and to incorporate it into the substrates. You need the coenzyme NADPH and a diflavin protein, the NADPH cytochrome P450 oxidoreductase .

In accordance with the multitude of toxins, there is a whole range of CYP 450. They have a low substrate specificity, which means that one enzyme can convert many substances (substrates). The expression of these enzymes is initiated by their substrates. It is understandable that pharmaceuticals which are broken down via the same CYP 450 influence each other in terms of their pharmacokinetics . Examples of this known from everyday life are:

  • Ingredients in grapefruit juice inactivate CYP 3A4 while it is induced by over-the-counter preparations containing St. John's wort. This enzyme also breaks down a large number of drugs, e.g. B. be prescribed for high blood pressure ( arterial hypertension ) ( verapamil , nifedipine ); but also anticonvulsants such as phenytoin and diazepam or antiarrhythmics such as amiodarone and many others.
  • Alcohol ( ethanol ) is broken down by the same microsomal ethanol oxidizing system (MEOS) as methanol or some antibiotics. As a result, the effects of these drugs can increase dangerously when alcohol is consumed.
  • Antibiotics such as rifampicin induce the increased expression of various CYP 450. As a result, active ingredients of the contraceptives (pill) are broken down more quickly and lose their effect.

genetics

Acetylators and metabolizers

The endowment of every single person with enzymes for biotransformation is different. Evolutionarily this variety has the advantage that with a poisonous effect on a population increases the chance that at least a few individuals are comfortable with it and survive. In everyday life it has been shown that some people break down various drugs faster or more slowly than others. The range of this fact ranges from carousing bets and Asians who are drunk after low amounts of alcohol to bladder cancer due to drug accumulation to fatal heart attacks due to non-metabolized heart drugs ( β-blockers : metoprolol ).

literature

Web links

Wiktionary: Biotransformation  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 510.
  2. ^ [1] Biotransformation on ChemgaPedia.
  3. ^ Reichel FX; Pocket Toxicology Atlas; 3. Edition; 2009; Thieme, Stuttgart-New York; P. 14 ff .; ISBN 978-3-13-108973-1
  4. ↑ [2] . Phase II reactions to ChemgaPedia.
  5. ↑ [3] . How the liver breaks down alcohol - quarks and co.