Cytochrome P-450 family

KIM, G.T., TSUKAYA, H., UCHIMIYA, H, The ROTUNDIFOLIA3 gene of Arabidopsis thaliana encodes a new member of the cytochrome P-450 family that is required for the regulated polar elongation of leaf cells, Genes Dev., 1998,12, 2381-91. 

C CNS CoA CYP-450 Cys Cytosine Central nervous system Coenzyme A Cytochrome P-450 family Cysteine... 

K. Sogawa, Y. Fujii-Kuriyama et al. (1993). A novel form of cytochrome P-450 family 4 in human polymorphonuclear leukocytes cDNA cloning and expression of leukotriene B cohydroxylase. J. Biol. Chem. 268, 9376-9380. 

The cytochrome P-450 family is the most important class of enzymes involved in drug metabolism. The nomenclature uses an Arabic numeral to denote the family, followed by a capital letter to designate a subfamily, followed by another Arabic numeral to denote an individual gene/enzyme. In humans five CYP450 isoforms are commonly involved in hepatic drug metabolism lA, 2C, 2D, 2E, and 3A. Table 3.3 presents a summary of substrate specificities and inhibitors for the common isoforms. 

Differences in metabolism among patients can lead to differences in susceptibility to ADRs e.g. patients with abnormal pseudocholinesterase levels have prolonged apnea after receiving succi-nylcholine patients with low activity of A-acetyl transferase are more likely to develop lupus-like reactions to procainamide, hydralazine, and isonia-zid and variants of the cytochrome P-450 family of enzymes can lead to altered metabolism of a variety of drugs, including antidepressants, antiarrhythmic agents, codeine, metoprolol terfenadine, cyclosporine, calcium channel blockers, and others (Peck et al 1993). 

Ropp JD, Gunsalus IC, Sligar SG (1993) Cloning and expression of a member of a new cytochrome P-450 family cytochrome p-4501in (CYPl 11) from Pseudomonas incognita. JBacteriol 175 6028-6037... 

N-Nitrosamines by themselves are not significant carcinogens. However, they are activated in the liver by a class of iron-containing enzymes (members of the cytochrome P-450 family). Activation involves the oxidation of a C—bond next to the amine nitrogen to a C—OH group. 

Enzyme system responsible for this reaction is localised in microsomal fraction (Maier et al., 1988 Kim et al., 1983) and belongs obviously to the cytochrome P-450 family. Derivatives of elymoclavine are analogously converted by C. paspali to respective lysergic acid derivatives (Philippi and Eich, 1984). Biotransformations of elymoclavine leading to its glycosides are described separately. 

Representative Phase I Biotransformation Reactions Catalyzed by the Cytochrome P-450 Family of Enzymes... 

Note Therapeutic drugs are listed as examples of foreign chemicals whose structures are modified by Phase I reactions, often by the addition of an oxygen atom. Some Phase I reactions, e.g., dechlmna-tion, do not involve oxygen. A few Phase I reactions are catalyzed by enzymes outside the cytochrome P-450 family one example is the conversion of ethyl alcdiol to acetalddiyde (not shown). 

In addition to the failures of biotransformation reactions to promote the elimination of some xenobiotics. Phase I reactions occasionally have the effect of increasing rather than reducing a chemical s toxicity. For example, several enzymes in the cytochrome P-450 family are known to convert foreign chemicals into electrophiles. Electrophiles are molecules that are deficient in electrons as such, they tend to react with molecules that are relatively electron-rich such as proteins, lipids, and DNA, which are essential to the health of cells. When a cellular molecule is attacked by an electrophile, its structure is altered, and its function is undermined (Chapter 7). 

Phenylpropanoids are biologically synthesized from phenylalanine as described above. Among them, cinnamic acid is synthesized directly from phenylalanine by phenylalanine ammonia-liase (PAL), and p-hydroxycinnamic acid p-coumaric acid) is synthesized from cinnamic acid by cinnamic acid 4-hydroxylase (C4H, an enzyme in the cytochrome P-450 family).The phenylpropanoid metabolic pathway is important for plants to synthesize lignin, and some phenylpropanoids are seen at junctions of cell wall polysaccharides such as hemicellulose and pectin. 

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