Cytochrome P450 enzymes metabolic activation

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Metabolism of Other Pharmacologically Active Compounds by Cytochrome P450 Enzymes... 

Metabolism of Other Pharmacologically Active Compounds by Cytochrome P450 Enzymes 449 Future Targets for Candidate Gene Studies 450 Genome Scans to Investigate Tobacco Dependence 450 Genomic Areas Linked with Susceptibility to Nicotine Dependence 451... 

The cytochrome P450 enzymes are responsible for the metabolism of a number of pharmacological agents. Inhibition of these enzymes could result in elevation of serum levels of agents that are dependent on the activity of P450 enzymes for metabolism. 

Generally, the liver is the center of drug metabolism, hence numerous drugs and methods to measure functional hepatic capacity are available. A host of these methods rely on the metabolic activity of cytochrome P450 enzymes, and some of the markers used include phenacetin, methacetin, trimethadione. 

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 cDNA expression systems can be used to address questions such as can human enzymes metabolize a xenobiotic What are the metabolites Can human enzymes activate a protoxin In order to adequately support a negative conclusion it is obvious that the range of cytochrome P450 enzymes examined needs to be as comprehensive as possible. 

The initial step is metabolic activation of butadiene to its reactive epoxide metabolites by multiple cytochrome P450 enzymes, including cytochrome P450 2E1 (CYP2E1). Butadiene is bioactivated to at least two genotoxic metabolites, epoxybutene and diepoxybutane. These two metabolites have been studied in detail by numerous laboratories. A third genotoxic epoxide metabolite of butadiene, epoxybutanediol, has not been quantified in animals but adducts to haemoglobin that are presumed to be derived from this epoxide have been detected in rats and humans exposed to butadiene. 

Certain furan derivatives show selective organ toxicity in animals. One such chemical is 4-ipomeanol (54 see Table 8 for structures), which is toxic to specific cells (Clara cells) in the lungs of treated animals (77MI10501). Administration results in bronchiolar cell necrosis, extensive pulmonary oedema and subsequent death of the animal. Experiments have shown that ipomeanol is localized within the Clara cell (77MI10501), which is considered to be rich in cytochrome P450 (78MI10505), an important enzyme complex for metabolism. The ipomeanol is then converted via the cytochrome P450 into an activated species that alkylates... 

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