Biotransformation refers to a process in metabolism in which substances that cannot be excreted are converted into excretable products by chemical processes.
What is biotransformation?
Biotransformation involves the conversion of lipophilic substances into more hydrophilic substances. The reactions required for biotransformation occur primarily in the liver. In the course of biotransformation, lipophilic substances are transformed into more hydrophilic substances. The transformation subsequently enables excretion. The reactions necessary for biotransformation occur predominantly in the liver. Overall, a biotransformation consists of two distinct phases.
Function and task
In the human organism, substances that cannot be excreted via the stool or urine repeatedly accumulate in the course of physiological metabolism. These substances are very often lipophilic (for example, steroid hormones and bile pigments), which means that they are not soluble in water, or only with great difficulty. Furthermore, the body also absorbs foreign substances or synthesized substances such as medications or drugs with food. If these substances were to accumulate in the body, it would be fatal. Therefore, it is necessary to transform them into a form that can be excreted. This process is called biotransformation. Biotransformation consists of two distinct phases: Phase I reactions insert functional groups into foreign substances or metabolites, with the help of the heme protein cytochrome P450 enzyme. Due to the large number of toxins, there is also a large number of CYP 450, with one enzyme being able to transform many substances. In the first phase, toxins are neutralized and subsequently broken down into small molecules. In the next phase, these are then made water-soluble and excreted via breath, urine or sweat secretion. In the second phase, the intermediate products or foreign substances from phase I are combined with water-soluble substances. This can increase their water solubility. In addition, the reaction products are detoxified and excreted. After phase II, transport processes take place via the lymphatic system, the bloodstream and transport proteins, although in some cases metabolism does not occur here. Furthermore, various reactions occur, such as the degradation of GSS6/GSH to glucomat, cysteine or N-acetylcysteine. Membrane transport is carried out with the help of special carriers, such as the multidrug resistance-related proteins. The products formed in phase II are called conjugates. These biologically active or toxic substances are not specifically recognized as such by the body. Rather, the process is due to the enzymes having quite low substrate specificity. As a result, reactions are induced in an entire group of substances.
Diseases and disorders
However, the process of biotransformation also entails risks. For example, even a harmless substance can also be transformed into a toxin. An example of this would be aflatoxin B1, which comes from a fungus known as Aspergillus flavus, which is found in poorly stored pistachios, peanuts, or corn. The molecule produced by the fungus is initially inactive and enters the liver with food. There it is changed by the cytochrome P450 enzyme into a metabolite that has a carcinogenic effect. When a toxic metabolite is formed from a substance by biotransformation, this process is known as toxification. Another example is methanol, which is not normally toxic. However, it is transformed into formaldehyde or formic acid by degradation. Morphine is transformed in the liver into what is known as morphine-6-glucuronide, which has an even more potent effect than morphine. Eise transformation effects are also called first-pass effects. The process also has an influence on drugs. Due to the metabolism, these lose activity and are extracted from the portal blood by the liver. However, toxicity may also result, an example of which would be the metabolism of paracetamol and alcohol. Since the breakdown of alcohol and some drugs occurs via the same microsomal ethanol-oxidizing system, the effects of drugs in combination with alcohol can be potentiated. Disturbances in biotransformation occur at three different levels:
- By increased or decreased activity of so-called microsomal enzymes (mainly in phase I).
- Due to disturbances in biliary excretion.
- Due to decreased uptake of xenobiotics into the cells of the liver.
The process of converting lipophilic substances into hydrophilic substances is also used for endogenous molecules such as bilirubin or steroid hormones. As a result, these are inactivated and subsequently excreted. In chronic liver insufficiency, however, estrogens cannot be inactivated or excreted, resulting in accumulation in the body. Bilirubin is formed during the breakdown of porphyrins. In higher concentrations it has a toxic effect and should therefore be eliminated by the organism. However, transport disorders can occur, including, for example, Gilbert-Meulengracht syndrome, Rotor syndrome or Dubin-Johnson syndrome. However, biotransformation disorders can also occur in premature or newborn infants. The glucuronidation capacity of the liver is not yet sufficiently developed in them, so that drugs or bilirubin can only be inadequately converted and excreted. In certain liver diseases such as cirrhosis or hepatitis, the activity of the biotransformation enzymes may also be impaired. In most cases, phase I reactions are then more affected than phase II reactions. Drugs are also metabolized and excreted at a slower rate in this case, thereby prolonging their half-life, which should also be taken into account therapeutically.
