Cytochrome P450 enzyme family

In silico estimation of metabolism is still an area of intense study and development. Accurate prediction of intrinsic clearance is still not possible with the currently available methods [15]. Most of the progress in this area has been focused on the mixed function oxidase cytochrome P450 enzyme family. Advances in this area have been focused on three areas (1) prediction of the cytochrome P450 (CYP) enzyme isotype that is responsible for the major metabolism, (2) prediction of the chemical site of a molecule that is most likely to undergo biotransformation by oxidative metabolism, and (3) structure-based docking studies of CYP enzyme substrate complexes. ... 

The key to many of these degradation processes is oxidative metabolism by the cytochrome P450 enzyme family [10]. Cytochrome P450 oxidation is most easy for electron-rich -electron systems, for example aromatic moieties or olefinic substructures, from which epoxides are generated. These epoxides are often potent electrophiles, intercalating into DNA and reacting with all kinds of nucleophile, for example nucleobases, amines, or thiols. Metabolic processes like this are the reason for the mutagenicity of many polycyclic arenes. 

TABLE 5—3. Cytochrome P450 Enzyme Family and Selected Substrates... 

In the liver, oxidation reactions are catalysed by a group of enzymes known as the microsomal mixed function oxidase system or the cytochrome P450 enzyme family. Oxidative reactions take place in many other tissues as well. 

The cytochrome P450 enzyme family contains at least 100 to 150 different isozymes with at least 40% sequence homology. These isozymes have different but overlapping specificities. The human enzymes are generally divided into six major subfamilies, and each of these is further subdivided. For example, in the naming of the principal enzyme involved in the oxidation of ethanol to acetaldehyde, CYP2E1, the CYP denotes the cytochrome P450 family, the 2 denotes the subfamily, the E denotes ethanol, and the 1 denotes the specific isozyme. 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

The most important enzymes in the liver for deactivating medications are called the cytochrome P450 enzymes. This is actually a family of related enzymes, and pharmacologists are constantly discovering new members of this family. 

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins. 

Phase I metabolic reactions involve oxidation, reduction, or hydrolysis of the parent molecule, resulting in the formation of a more polar compound. Phase 1 reactions are mediated by the cytochrome P450 (GYP) family of enzymes. While metabolism used to be thought of as the body s detoxification process, phase I metabolites may be equally or even more pharmacologically active than the parent compound. Drug metabolism in general, and CYP-based mechanisms in particular, are discussed in detail in Chapter 5. 

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

As total inhibitors of the P450 enzyme family, 1-Aminobenzotriazole (Lee and Slattery 1997) and Proadifen (SKF525A) (Lee et al. 1998) are suitable to distinguish from non-cytochrome P450 mediated pathways. 

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