Metabolism of drugs in the liver

Phase 1

The main system that metabolizes drugs is located in the microsomal fraction of hepatocytes (in the smooth endoplasmic reticulum). It includes monooxygenases with a mixed function, cytochrome C-reductase and cytochrome P450. The cofactor is the reduced NADPH in the cytosol. The drugs are subjected to hydroxylation or oxidation, which provide an increase in their polarization. An alternative reaction of phase 1 is the conversion of ethanol to acetaldehyde using alcohol dehydrogenases, which are detected mainly in the cytosol.

Induction of enzymes is caused by barbiturates, alcohol, anesthetics, hypoglycemic and anticonvulsants (griseofulvin, rifampicin, glutetimide), phenylbutazone and meprobamate. Induction of enzymes may be the cause of an increase in the liver after the initiation of drug therapy.

Phase 2

Biotransformation to which drugs or their metabolites are exposed, consists in their conjugation with small endogenous molecules. Enzymes providing it are non-specific for the liver, but are found in it in high concentrations.

Active transport

This system is located on the biliary pole of the hepatocyte. Transport is carried out with energy consumption and depends on the degree of saturation with the transported substance.

Excretion with bile or urine. Products of biotransformation of drugs can be excreted with bile or urine; The method of isolation is determined by many factors, some of which have not yet been studied. Highly polar substances, as well as metabolites that have become more polar after conjugation, are excreted with bile in unchanged form. Substances with a molecular mass above 200 kDa are also excreted with bile. The lower the molecular weight of the substance, the more it is excreted in the urine.

[1], [2], [3], [4], [5], [6]

Cytochrome P450 system

The hemoprotein system P450, located in the endoplasmic hepatocyte network, provides a metabolism of drugs; at the same time toxic metabolites are formed. At least 50 isoenzymes of the P450 system have been identified, and there is no doubt that there are even more of them. Each of these enzymes is encoded by a separate gene. In humans, the metabolism of drugs is provided by cytochromes belonging to three families: P450-I, P450-II and P450-III. Each molecule of cytochrome P450 has a unique site for the substrate, capable of binding drugs (but not all). Each cytochrome is able to metabolize several drugs. In this case, the genetic differences in the catalytic activity of the enzyme can cause the development of idiosyncrasy on the drug. For example, abnormal expression of the P450-I I-D6 isoenzyme shows a worsening of the metabolism of debrisoquine (antiarrhythmic drug). The same enzyme system is metabolized by most beta-blockers and antipsychotics. The disturbance of the metabolism of debrisoquine can be determined by revealing the sites of mutant genes of cytochrome P450-II-D6 by polymerase chain reaction (PCR). This allows us to hope that in the future it will be possible to predict pathological reactions to drugs.

The P450-II-E1 isoenzyme is involved in the formation of electrophilic products of paracetamol metabolism.

Isozyme P450-III-A is involved in the metabolism of cyclosporine, as well as other drugs, especially erythromycin, steroids and ketoconazole. Polymorphism of the isoenzyme P450-II-C affects the metabolism of mephenitoin, diazepam and many other drugs.

[7], [8], [9], [10], [11], [12], [13],

Induction of enzymes and drug interactions

An increase in the content of enzymes of the cytochrome P450 system as a result of induction leads to an increase in the production of toxic metabolites. It was revealed that in the transplanted liver expression of the enzymes of the P450 system and its induction by phenobarbital are retained in hepatocytes irrespective of their position in the acinus or the state of the sinusoids.

When two active drugs compete for one binding site on the enzyme, the metabolism of the drug with less affinity slows down and its duration increases.

Ethanol induces the synthesis of P450-II-E1 and thereby increases the toxicity of paracetamol. The toxicity of paracetamol is also increasing with isoniazid, which also induces the synthesis of P450-II-E1.

Rifampicin and steroids induce P450-III-A metabolizing cyclosporin. This explains the decrease in the level of cyclosporine in the blood when it is taken in combination with these drugs. Cyclosporine, FK506, erythromycin and ketoconazole compete for the binding site of the P450-III-A isoenzyme, therefore the level of cyclosporin in the blood increases with the administration of these drugs.

Omeprazole induces P450-IA. This isoenzyme plays an important role in biotransformation of procarcinogens, carcinogens and many medicinal substances. Perhaps taking omeprazole increases the risk of developing tumors.

In the future, it will be possible to identify P450 profiles and identify individuals at high risk of adverse drug reactions. To modify the P450 profile, selective inhibitors or inducers can be used.

Immune hepatotoxicity

Metabolite can be a hapten for proteins of liver cells and cause their immune damage. The enzymes of the P450 system can participate in this process. On the membrane of hepatocytes there are several isoenzymes P450, the induction of which can lead to the formation of specific antibodies and immune damage to the hepatocyte.

In hepatitis caused by halothane, antibodies to liver protein microsomes, damaged by this drug, are detected in the serum of patients.

Idiosyncrasy to diuretics and thienyl acid is accompanied by the appearance of autoantibodies interacting with liver and kidney microsomes (anti-LKM II). The antigen to which these antibodies are directed belongs to the family P450-II-C, which also participates in the metabolization of thienyl acid.