Inducer enzyme

The efficiency of inactivation by covalent bond formation vs release of the reactive species into solution has been described by its partition ratio. The most efficient inactivators have catalytic partition ratios of 0, in which case each inhibitor molecule leads to inactivation of the enzyme. To this date, many of these inhibitors have been designed, and alternative names like suicide substrate, Trojan Horse inactivator, enzyme induced inactivator, inhibitor, and latent inactivator have been used for this class of inhibitors. A number of comprehensive reviews are available (26—32). 

Scheme 1, Enzyme-induced cyclizations of squalene oxide (2) (a) and the Stork-Eschenmoser hypothesis (b).

The catalytic cycle of the Na+/K+-ATPase can be described by juxtaposition of distinct reaction sequences that are associated with two different conformational states termed Ei and E2 [1]. In the first step, the Ei conformation is that the enzyme binds Na+ and ATP with very high affinity (KD values of 0.19-0.26 mM and 0.1-0.2 pM, respectively) (Fig. 1A, Step 1). After autophosphorylation by ATP at the aspartic acid within the sequence DKTGS/T the enzyme occludes the 3 Na+ ions (Ei-P(3Na+) Fig. la, Step 2) and releases them into the extracellular space after attaining the E2-P 3Na+ conformation characterized by low affinity for Na+ (Kq5 = 14 mM) (Fig. la, Step 3). The following E2-P conformation binds 2 K+ ions with high affinity (KD approx. 0.1 mM Fig. la, Step 4). The binding of K+ to the enzyme induces a spontaneous dephosphorylation of the E2-P conformation and leads to the occlusion of 2 K+ ions (E2(2K+) Fig. la, Step 5). Intracellular ATP increases the extent of the release of K+ from the E2(2K+) conformation (Fig. la, Step 6) and thereby also the return of the E2(2K+) conformation to the EiATPNa conformation. The affinity ofthe E2(2K+) conformation for ATP, with a K0.5 value of 0.45 mM, is very low. 

Acetaminophen, which depletes hepatic glutathione, does not potentiate the toxicity of methyl parathion in mice. A possible mechanism of action may be competition between acetaminophen and methyl parathion for mixed function oxidases and subsequent prevention of activation of methyl parathion to methyl paraoxon (Costa and Murphy 1984). Diethyl maleate, an agent that depletes cytosolic glutathione and is not an enzyme inducer, potentiates toxicity of methyl parathion in mice (Mirer et al. 1977). 

Substrates and enzymes induce mutual conformational changes in one another that facihtate substrate recognition and catalysis. 

Proteases are crucial enzymes induced by HIV to alter the physiology of the central nervous system. Indeed, proteases participate in brain infection, helping infected peripheral cells to cross the blood-brain barrier, as well as in the viral neuropathogenesis as will be later discussed. We will first describe examples of... 

Kaneko T, Wang P-Y, Sato A. 1994. Enzymes induced by ethanol differently affect the pharmacokinetics of trichloroethylene and 1,1,1-trichloroethane. Occup Environ Med 51 113-119. 

Wettasinghe, M. et al.. Phase II enzyme-inducing and antioxidant activities of beetroot Beta vulgaris L.) extracts from phenotypes of different pigmentation, J. Agric. Food Chem., 50, 6704, 2002. 

Maintain plasma levels between 30 and 40 mg/L ° Taper dose if ICP well controlled for 24-48 h ° Potent CYP 450 enzyme inducer... 

Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF vasodilation and neurohormonal antagonism of endothelin.9 Nitric oxide s production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is up-regulated in the setting of HF, likely due to increased levels of angiotensin II, norepinephrine, and multiple cytokines. In HF, the physiologic response to nitric oxide appears to be blunted, which contributes to the imbalance between vasoconstriction and vasodilation. 

Monotherapy 20 hours Concurrent enzyme inducers 11-16 hours... 

Lamotrigine Modulate sodium channels Loading dose Not recommended due to increased risk of rash Maintenance dose 1 50-800 mg/day in 2-3 divided doses. Doses should be initiated and titrated according to the manufacturer s recommendations to reduce the risk of rash Half-life Not established Monotherapy 24 hours Concurrent enzyme inducers 12-15 hours Concurrent enzyme inhibitors 55-60 hours Apparent volume of distribution 1.1 L/kg Protein binding 55% Primary elimination route Hepatic Ataxia, drowsiness, headache, insomnia, sedation Rash... 

Administer supplemental vitamin K during the eighth month of pregnancy to women receiving enzyme-inducing antiepileptic drugs... 

Conversely, the metabolism of divalproex can be increased by enzyme-inducing drugs such as carbamazepine and phenytoin, while divalproex may simultaneously slow metabolism of the other agents.35... 

Buspirone generally is well tolerated and does not cause sedation. Most common side effects include dizziness, nausea, and headaches. Drugs that inhibit CYP3A4 (e.g., verapamil, diltiazem, itraconazole, fluvoxamine, nefa-zodone, and erythromycin) can increase buspirone levels. Likewise, enzyme inducers such as rifampin can reduce buspirone levels significantly. Bupirone may increase blood pressure when coadministered with an monoamine oxidase inhibitor (MAOI). 

Half-life Monotherapy 7-9 hours Concurrent enzyme inducers 2.5-4.5 hours Apparent volume of distribution 0.6-0.8 L/kg Protein binding 96% Primary elimination Not established Dizziness, somnolence, irritability, slowed thinking ... 

The primary metabolism of an organic compound uses a substrate as a source of carbon and energy. For the microorganism, this substrate serves as an electron donor, which results in the growth of the microbial cell. The application of co-metabolism for bioremediation of a xenobiotic is necessary because the compound cannot serve as a source of carbon and energy due to the nature of the molecular structure, which does not induce the required catabolic enzymes. Co-metabolism has been defined as the metabolism of a compound that does not serve as a source of carbon and energy or as an essential nutrient, and can be achieved only in the presence of a primary (enzyme-inducing) substrate. 

Ramos-Gomez, M., M. K. Kwak, P. M. Dolan et al. 2001. Sensitivity to carcinogenesis is increased and chemo-protective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98(6) 3410—3415. 

The reactions presented in this chapter show clearly that enzyme-triggered domino reactions offer a great potential in asymmetric synthesis. It remains to be seen, whether this methodology becomes a general tool, since the design of such enzyme-induced domino processes is not trivial. Nonetheless, this emerging field obviously has great potential. 

BA trans-3.4-dihvdrodiol cannot be separated from BA trans-8.9-dihydrodiol in several HPLC conditions (27-29). Quantification of BA trana-3,4-dihydrodiol by HPLC can only be accomplished after converting the 3,4-dihydrodiol to its diacetate (25.26). The BA trans-3.4-dihydrodiol formed in BA metabolism by liver microsomes from pheno-barbital-treated rats was determined to have a 3R,4R/3S,4S enantiomer ratio of 69 31 (30). Recently we have determined the optical purity of the BA trans-3.4-dihvdrodiol formed in the metabolism of BA by three liver microsomes prepared from untreated rats and rats that had been pretreated with an enzyme inducer. As shown in Table II, cytochrome P-450 isozymes contained in liver microsomes from 3-methylcholanthrene- or phenobarbital-treated rats had similar stereoselectivity toward the 3,4-double bond of BA. BA trans-3.4-dihydrodiol is formed via the 3,4-epoxide intermediate (31). 

In contrast to the metabolism of BA and BaP, the 5,6-dihydrodiols formed in the metabolism of DMBA by liver microsomes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated rats are found to have 5R,6R/5S,6S enantiomer ratios of 11 89, 6 94, and 5 95, respectively (7.49 and Table II). The enantiomeric contents of the dihydrodiols were determined by a CSP-HPLC method (7.43). The 5,6-epoxide formed in the metabolism of DMBA by liver microsomes from 3MC-treated rats was found to contain predominantly (>97%) the 5R,6S-enantiomer which is converted by microsomal epoxide hydrolase-catalyzed hydration predominantly (>95%) at the R-center (C-5 position, see Figure 3) to yield the 5S,6S-dihydrodiol (49). In the metabolism of 12-methyl-BA, the 5S,6S-dihydrodiol was also found to be the major enantiomer formed (50) and this stereoselective reaction is similar to the reactions catalyzed by rat liver microsomes prepared with different enzyme inducers (unpublished results). Labeling studies using molecular oxygen-18 indicate that 5R,68-epoxide is the precursor of the 5S,6S-dihydrodiol formed in the metabolism of 12-methyl-BA (51). 

Singh, A. and Kaplan, D.L. In Vitro Enzyme-Induced Vinyl Polymerization. Vol. 194, pp. 211-224. 

Phenobarbital is a potent enzyme inducer and interacts with many drugs. The amount of phenobarbital excreted renally can be increased by giving diuretics and urinary atkalinizers. 

Enzyme inducers may decrease topiramate serum levels. 

At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-ene-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. At least 67 cases of hepatotoxicity have been reported, and most deaths were in mentally retarded children less than 2 years old who were receiving multiple drug therapy. 

Twice-daily dosing is reasonable, but children and patients taking enzyme inducers may require three-or-four-times-daily dosing. 

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