Enzyme, drug deactivation

The EHs are a family of enzymes that deactivate epoxides by catalyzing their hydration to form diols (5) (Fig. 6.9). Two members of this family are associated with drug... 

It may be fair to ask, Is this much ado about nothing Although test tube studies have shown that particular drugs interact, it is seldom that this causes problems for patients taking the medications. For example, the antidepressant fluvoxamine inhibits the enzyme that deactivates the antipsychotic haloperidol (Haldol). Does this mean that fluvoxamine and haloperidol cannot be taken together By no means. Although this would probably raise the blood level of haloperidol somewhat, the main effect if any would be that a smaller dose of haloperidol would be more effective. 

Avoids first-pass effect (drug deactivation by digestive and liver enzymes)... 

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

Thromboxane A-2 has been implicated in a number of disorders of the circulatory system including coronary artery spasms, unstable angina pectoris, traumatic and endotoxic shock, and heart attacks. It is formed normally very near its receptors and is rapidly deactivated by metabolizing enzymes so circulating levels are quite low. Furthermore, it is opposed in its actions by the prostacyclins. When these controls are defective, pathology results and drugs can be the resort in attempts to restore the normal healthy balance. For one example, furegrelate (6) is a throm-... 

Over the past few years there have been an increasing number of reports of diseases that are becoming resistant to previously effective drug treatments. This resistance is often due to the presence of enzymes that bring about chemical modification of the drug to an inactive form, e.g. /S-lactamase enzymes deactivate (6-lactam antibiotics by their conversion to penicillanic acid. 

The anticancer drug 6-mercaptopurine is deactivated by the enzyme xanthine oxidase. A cancer patient being treated with 6-meicaptopurine develops hyperuricemia, and the physician decides to give the patient allopurinoL... 

Drug Interactions. No modern discussion of the history of antidepressants would be complete without mention of the debate regarding potential drug interactions. As discussed more fully in Chapter 2, medications may interact in several ways, and their interactions may be helpful or harmful. The antidepressant debate has focused on the way these drugs influence the liver s ability to metabolize and thus deactivate other drugs. In particular, it is the impact of antidepressants on the liver s cytochrome P450 family of enzymes that has been so extensively discussed. 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

It was previously thought that 5-FU inhibits the enzyme by classical competitive inhibition. However, it was found that 5-FU is a transition-state substrate, and it forms a covalent complex with tetrahydrofolate and the enzyme in the same way that the natural substrate does. The reaction, however, will not go to completion, since the fluoro-uridine derived from the antimetabolite remains attached to the enzyme, and the latter becomes irreversibly deactivated. Recovery can occur only through the synthesis of new enzyme. Fluorouracil is used in the treatment of breast cancer and has found limited use in some intestinal carcinomas. Unfortunately, this drug has the side effects usually associated with antimetabolites. Its prodrug, fluorocytosine (8.35, which is also an antifungal agent) is better tolerated. 

The use of zeolites to mirror biological systems is feasible in the two cases studied. Further work is in progress to extend the enzyme investigation. This is concerned with the replacement of Zn2+ by other metal ions, particularly those which are known to deactivate the enzyme. The work on skins will be extended to study vehicular transport of drugs in relation to known pharmaceutical preparations. 

Drug-resistant bacteria inactivate /3-lactam antibiotics by hydrolyzing the amide linkage of the lactam ring. Augmentin consists of a /3-lactam antibiotic (amoxicillin) and potassium clavulanate, a compound that blocks the enzyme responsible for the hydrolysis. This combination enables the amoxicillin to avoid being deactivated by the enzyme. 

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