Induction enzyme

Details of some inducible P450 forms that play key roles in the metabolism of xenobiotics are shown in Table 2.4. P450s belonging to family lA are induced by various lipophilic planar compounds including PAHs, coplanar PCBs, TCDD and other dioxins, and beta naphthoflavone (Monod 1997). As noted earlier, such planar compounds are also substrates for P450 lA. In many cases, the compounds induce the enzymes that will catalyze their own metabolism. Exceptions are refractory compounds such as 2,3,7,8-TCDD, which is a powerful inducer for P450 lA but a poor substrate. 

The induction of P450s belonging to family CYP2 by phenobarbital and other inducing agents is accompanied by proliferation of the endoplasmic reticulum and 

Family Individual Forms Induced by Typical Substrates 

CYP2 llBl, 11B2 Phenobarbital Wide range 

The induction process can operate at different levels. The most important mechanisms for particular isoforms are summarized as follows  

Dorrington and colleagues [60] first demonstrate the ability of FSH to induce aromatases in granulosa cells. Treatment with FSH from various mammalian species increases aromatase activity in granulosa cells from rats [61]. It is known that the aromatase system is comprised of a specific form of cytochrome P-450 and the fla-voprotein NADPH-cytochrome P-450 reductase. Recently, the cytochrome P-450 aromatase enzyme has been cloned from human placenta, thus allowing further investigation of the molecular mechanisms that mediate the regulation of aromatase activity [62]. 

As previously mentioned, many of the enzymes involved in xenobiotic metabolism are inducible. Inducibility allows for more enzymatic activity, thereby ensuring an adequate detoxication response however, it also provides a mechanism whereby an activation pathway may be increased. This occurs in the example given earlier of the combined effects of ethanol and acetaminophen. When CYP2E1 is induced by ethanol prior to administration of acetaminophen, subsequent activation of acetaminophen to NAPQI is prevalent however, without induction by ethanol, CYP2E1 is not the predominant enzyme for metabolizing acetaminophen, and detoxication is favored. Interestingly, simultaneous administration decreases the toxicity of acetaminophen because both are substrates for 2E1 ethanol acts as a competitive inhibitor, thereby blocking the activation of acetaminophen. 

Other actions of methylene blue include monoamine oxidase inhibition, which can cause dangerous interactions with certain other drugs. Flowever, it also has potential to treat malaria and Alzheimer s disease, the latter as a formulation named Rember . Its activity in Alzheimer s disease is thought to depend on converting an abnormal tangled form of a protein in the brain back to the normal form, although the mechanism for this is not clear. 

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Toxicological studies have demonstrated that there are no important problems with fluconazole. Therapeutic doses of fluconazole may cause enzyme induction in the Hver. This suggests that interactions with other dmgs cannot be excluded. The side effects are similar to those of itraconazole and include nausea, headache, and vertigo. Occasionally, increased Hver enzymes may be noted. Like itraconazole, fluconazole is contraindicated during pregnancy. 

The interactions may be physicochemical without the participation of biological mechanisms for example, deep lung exposure to highly soluble irritative gases, such as sulfur dioxide, may become enhanced due to adsorption of the gas onto fine particles. Biological interactions may occur at all stages and body sites. For example, toxicity is increased when adverse effects are due to some reactive metabolic intermediate and exposure to another agent stimulates its metabolic activation (enzyme induction). 

Agarwal et al. 1978), the quantification of these specific enzymes may indicate that exposure to endosulfan has occurred. Blood tests, such as decay curves for aminopyrine in plasma, which are semiquantitative indices of liver enzyme induction, have been used successfully in the past to demonstrate enzyme induction in pesticide-exposed workers. Because numerous chemicals found at hazardous waste sites also induce these hepatic enzymes, these measurements are not specific for endosulfan exposure. However, measurements of enzyme activity, together with the detection of the parent compound or its metabolites in tissue or excreta, can be useful indicators of exposure. All of these potential biomarkers require further verification in epidemiological studies. Further studies with focus on the development of methods to separate and measure the estrogenicity of endosulfan in in vitro assays would be valuable since these assays are more sensitive and discriminative than other conventional biomarkers. Preliminary results have been presented by Sonnenschein et al. (1995). 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

Many of these compounds—puromycin and cycloheximide in particular—are not cfinically useful but have been important in elucidating the role of protein synthesis in the regulation of metabolic processes, particularly enzyme induction by hormones. 

Another example of enzyme induction involves CYP2E1, which is induced by consumption of ethanol. This is a matter for concern, because this P450 metabohzes certain widely used solvents and also components found in tobacco smoke, many of which are established carcinogens. Thus, if the activity of CYP2E1 is elevated by induction, this may increase the risk of carcinogenicity developing from exposure to such compounds. 

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

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