Cytochrome P450 (CYP450) is an enzyme responsible for the conversion of many drugs. The metabolism of many classes of drugs is associated with the cytochrome P450 isoforms: antihistamines, retroviral protease inhibitors, benzodiazepines, calcium channel blockers and many others. The inhibition of the function of this enzyme leads to the accumulation in the body of substances metabolized in this way, which can lead not only to the development of toxic effects in individual patients, but also to the seizure of drugs which affect P450 activity in the pharmaceutical market.

It is known that the main increase in the cost of development of a new drug occurs at its final stage, with a direct study of its properties in a living organism (adsorption, distribution, metabolism, excretion, toxicity). Therefore, pharmaceutical companies prefer to look for these parameters on in vitro models. Astex Technology researchers have established the structure of human cytochrome 3A4 and other related enzymes. The data obtained will make it possible to screen the metabolic properties of new drugs in silico on the basis of an analysis of their structure.

The effects of cytochrome P450 are associated with its catalytic effect on the attachment of various chemical groups to molecules during metabolic transformations. About 55 different cytochrome P450 isoforms have been found in the human body, each encoded by a separate gene. Cytochromes are divided into families (indicated by numbers), subfamilies (indicated by letters) and isoforms (indicated by numbers).

One of the most important problems associated with cytochrome P450 and capable of delaying the introduction of drugs into clinical practice, limiting their use and even therapy ineffective in clinical practice, is the inhibition of enzyme function, which leads to the accumulation of toxic products during metabolism. The inhibition of the function of cytochrome P450 under the action of inhibitors of liver enzymes (for example, antifungal drugs - ketoconazole or itraconazole, which are strong inhibitors of cytochrome P450, etc.) leads to an increase in the half-life of drugs metabolized by cytochrome P450. On the contrary, the induction of the function of cytochrome P450 under the action of inducers of hepatic enzymes (for example phenobarbital) leads to a shortening of the half-life of other drugs and, consequently, to the need to increase their dosages.

At the initial stage of cytochrome research, their structure and functions were studied on the basis of the analysis of the bacterial cytochrome P450, which has a number of fundamental differences compared to mammalian cytochromes. Therefore, an important scientific discovery was the work of P. Williams et al., As a result of which the structure of the rabbit cytochrome P450 isoform 2C5 was deciphered. Subsequently, R. Williams continued to study the structure of human cytochrome P450 using the same technique at Astex (Cambridge, UK). Following research carried out in late 2001, the structure of human cytochrome 2C9 was deciphered. Currently, Astex has provided preliminary information on the structure of cytochrome 3A4, which metabolizes most drugs used in clinical practice.

Usually, when studying families of protein enzymes, it is not necessary to establish the structure of each protein in the family, because in many cases, for practical purposes, it is enough to create a model based on the example of the closest related molecules. However, for cytochrome P450, this principle was not entirely applicable. For example, the structure of the protein chains 2C9 and 2C19 is 90% identical, while small but fundamental differences in the active centers modify the specificity of the substrate.

At present, given the high frequency of prescribing a combination therapy with several drugs, it is particularly important to pay attention to their possible interactions, including according to changes in the function of cytochrome P450.

Knowledge of the structure of cytochromes can play an important role in various areas of drug research, including the development of new drugs for the treatment of tuberculosis. The genome of mycobacterium tuberculosis has been found to contain genes encoding 20 different P450 cytochromes, including enzymes which are the target of action of antifungal drugs. On this basis, azole antimycotics could later become the next generation of tuberculosis chemotherapy agents. Interestingly, of the antifungal drugs tested for systemic use, only fluconazole can be used, which has been shown to be ineffective against mycobacterium tuberculosis. Topical antimycotics are not suitable for the treatment of tuberculosis because they inhibit the cytochromes of the human body.

It is assumed that as new information about the structure of cytochrome P450 accumulates, the process of creating new anti-TB drugs, whose mechanism of action is associated with cytochrome P450, and which have not pronounced metabolic effects, will be greatly simplified.