Biotransformation of drugs by phase 1 and phase 2 reactions
Phase 1 reactions Oxidative reactions involving N- and O-dealkylation, aliphatic and aromatic hydroxylation, N- and S-oxidation, deamination.
Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation.
Classification of the cytochrome P450 enzymes
These enzymes have been classified according to the degree of structural similarity in their amino acid structures (the so-called sequence homology). Thus the closer the enzymes are from both the phylogenic and functional point of view, the more likely they are to be a member of the same enzyme family with a sequence homology of at least 40%. The enzymes are further grouped into subfamilies (isozymes) which are designated by the letters A, B, C, D, E, F. All enzymes in the same subfamily have a sequence homology of at least 55%. The final number designates the gene that codes for a specific enzyme (1, 2, 3, 4, 5, 6, 7, etc.). With regard to the metabolism of the psychotropic drugs, cytokines 1A2, 2C19, 2D6, 3A3/4 are of primary importance.
The cytochrome P450 enzymes are divided into two major groups, namely the ‘‘steroidogenic’’ enzymes (which are the phylogenically older type and are responsible for the synthesis of steroids and related compounds comprising the cell wall) and the ‘‘xenobiotic’’ type (located in the smooth endoplasmic reticulum and involved in the metabolism of foreign, or xenobiotic, compounds which include all drugs). The following list summarizes the types of compounds metabolized by the main groups of P450 enzymes:
. Steroidogenic type – steroids, bile acids, cholesterol, prostaglandin biosynthesis.
. Xenobiotic type – drugs, toxins, carcinogens, mutagens.
It should be noted that the genetic information for the P450 enzymes is present throughout in all tissues, but knowledge of the role of the enzymes in tissues other than the liver and gastrointestinal tract is unclear. For example, cytochrome P450 2D6 is found in the brain where it is linked to the dopamine transporter. Whether a deficit in the activity of this enzyme is responsible for predisposing some individuals to Parkinson’s disease is a matter of conjecture.
Phase 1 reactions Oxidative reactions involving N- and O-dealkylation, aliphatic and aromatic hydroxylation, N- and S-oxidation, deamination.
Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation.
Classification of the cytochrome P450 enzymes
These enzymes have been classified according to the degree of structural similarity in their amino acid structures (the so-called sequence homology). Thus the closer the enzymes are from both the phylogenic and functional point of view, the more likely they are to be a member of the same enzyme family with a sequence homology of at least 40%. The enzymes are further grouped into subfamilies (isozymes) which are designated by the letters A, B, C, D, E, F. All enzymes in the same subfamily have a sequence homology of at least 55%. The final number designates the gene that codes for a specific enzyme (1, 2, 3, 4, 5, 6, 7, etc.). With regard to the metabolism of the psychotropic drugs, cytokines 1A2, 2C19, 2D6, 3A3/4 are of primary importance.
The cytochrome P450 enzymes are divided into two major groups, namely the ‘‘steroidogenic’’ enzymes (which are the phylogenically older type and are responsible for the synthesis of steroids and related compounds comprising the cell wall) and the ‘‘xenobiotic’’ type (located in the smooth endoplasmic reticulum and involved in the metabolism of foreign, or xenobiotic, compounds which include all drugs). The following list summarizes the types of compounds metabolized by the main groups of P450 enzymes:
. Steroidogenic type – steroids, bile acids, cholesterol, prostaglandin biosynthesis.
. Xenobiotic type – drugs, toxins, carcinogens, mutagens.
It should be noted that the genetic information for the P450 enzymes is present throughout in all tissues, but knowledge of the role of the enzymes in tissues other than the liver and gastrointestinal tract is unclear. For example, cytochrome P450 2D6 is found in the brain where it is linked to the dopamine transporter. Whether a deficit in the activity of this enzyme is responsible for predisposing some individuals to Parkinson’s disease is a matter of conjecture.
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