18-Hydroxylase, inhibition

Disulfiram produces a variety of adverse effects, which commonly include drowsiness, lethargy, and fatigue (Chick 1999). Other more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, are rare. Psychiatric effects of disulfiram are also uncommon. They probably occur only at higher dosages of the drug and may result from the inhibition by disulfiram of a variety of enzymes in addition to ALDH. Included among the enzymes inhibited by disulfiram is dopamine P-hydroxylase, inhibition of which increases dopamine levels, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and occasionally may result in psychotic or depressive symptoms in patients without schizophrenia. 

Adrenolytic Agent Mitotane 11 P-hydroxylase. Inhibits steroidogenesis intermittently 2-6 g/day in 3-4 Gl intolerance (high Used primarily for adrenal... 

Introduction of chlorine or bromine into the 3- and/or 4- positions of the side chain yields more potent compounds in terms of hypotension in rats and dopamine p- hydroxylase inhibition (31. 32). The analog YP-279 (XXXV) is also hypotensive in rats but is said not to affect brain norepinephrine biosynthesis unlike fusaric acid or dibromofusaric acid (33-35). Fusaric acid amide (bupicomide, Sch 10595, XXXVI) is clinically effective at 300 to 1800 mg per day and is said to have hemodynamic effects similar to hydralazine (36. 37). The amide is... 

Siddiq, A., Ayoub, I.A., Chavez, J.C., et al. (2005) Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J. Biol. Chem., 280,41732-41743. 

Urenjak, J. and Obrenovitch, T. P. Kynurenine 3-hydroxylase inhibition in rats Effects on extracellular kynurenic acid concentration and N-methyl-D-aspartate-induced depolarisation in the striatum, J. Neurochem. 2000, 75, 2427-2433. 

Comish HH, Ryan RC. 1965. Metabolism of benzene in nonfasted, fasted, and aryl-hydroxylase inhibited rats. Toxicol Appl Pharmacol 7 767-771. 

Evidence suggests that elevated levels of the tricarboxylic acid cycle intermediates fumarate and succinate (the latter a product of hydroxylase catalysis) in some tumors may lead to activation of the HIF system via hydroxylase inhibition (97,98). Both succinate and fumarate are PHD2 inhibitors competing with 20G for binding to Fe(II) (99, 100). 

Metyrosine (23, a-methyl-L-tyrosine), a norepinephrine biosynthesis inhibitor, is in limited clinical use to help control hypertensive episodes and other symptoms of catecholamine overproduction in patients with the rare adrenal tumor pheochromocytoma (10). Metyrosine, a competitive inhibitor of tyrosine hydroxylase, inhibits the production of catecholamines by the tumor. Although metyrosine is useful in treating hypertension caused by excess catecholamine biosynthesis... 

Anden, N. E., Corrodi, H., Dahlstrom, A., Euxe, K., Hogfelt, T. Effects of tyrosine hydroxylase inhibition on the amine levels of central monoamine neurons. Life Sci. 1966, 5, 561—568. 

Borges CR, Geddes T, Watson JT, Kuhn DM (2002) Dopamine biosynthesis is regulated by S-glutathionylation. Potential mechanism of tyrosine hydroxylase inhibition during oxidative stress. J Biol Chem 277 48295-302... 

Deficiency of 21-hydroxylase inhibits the synthesis of glucocorticoids (e.g., cortisol) and mineralocorticoids (e.g., aldosterone), leading to overproduction of testosterone in the adrenal glands and underproduction of cortisol. The latter effectively increases adrenocorticotropic hormone (ACTH), which stimulates the adrenals to grow and synthesize steroids, exacerbating the testosterone overproduction. This leads to masculinization of females. 

Kunert, M.E, R.J. Roman, J.R. Faick, and J.H. Lombard (2001). Differential effect of cytochrome P-450 omega-hydroxylase inhibition on Oj-induced constriction of arterioles in SHR with early and established hypertension. Microcirculation 8,435-443. 

Holsztynska, E.J. and D.J. Waxman (1987). Cytochrome P-450 cholesterol 7a-hydroxylase Inhibition of enzjnne deactivation by structurally diverse calmodulin antagonists and phosphatase inhibitors. Arch. Biochem. Biophys. 256, 543-559. 

Jl. Jequier, E., Lovenberg, W., and Sjoerdsma, A., Tryptophan hydroxylase inhibition The mechanism by whicii p-chlorophenylalanine depletes rat brain serotonin. Mol. Pharmacol. 3, 274—278 (1967). 

For example, 4-hydroxy benzyl cyanide is an IMBI that can inhibit dopamine jS-hydroxylase. Inhibition of this enzyme decreases production of epinephrine and it is hoped that this IMBI will turn out to be useful in reducing sympathetic tone (Baldoni, Villafranca and Mallettee, 1980). 

Metyrapone, 2-methyl-l,2-di-3-pyridyl-l-pro-panone, is a potent reversible inhibitor (Dominguez and Samuels 1963, Sanzari and Peron 1966, Satre and Vignais 1974) of the and cytochrome P-450iip-hydroxylase enzyme system of the adrenal cortex. A quantitative structure activity relationship has been established between 5-hydro-xytryptamine receptor agonist activity of 8-hydro-xy-2-alkylamino)tetralins and adrenal cortical lip-hydroxylase inhibition potency of metyrapone derivatives and the van der Waals volume of the compound (Singh 1986). 

In a series of 5 alkylplcolinic acids, to vitro p-hydroxylase inhibiting activity was maximum with the n-pentyl analog (XVI). This analog was also the most potent in reducing blood pressure in anesthetized rabbits, but with longer chain analogs the two activities did not correlate ... 

Tyrosine hydroxylase inhibition - in vitro using bovine adrenal tyrosine kinase at 200.0 pM. 95... 

BIOLOGICAL ACTIVITY Catechol 0-methyltransferase inhibitor [8024,8025, 8040] pharmacology [6828] antimelanoma and skin depigmentation [6778] antihypertensive [8041] tyrosine hydroxylase inhibition [8042]. 

Hsieh, M.M., Linde, N.S.,Wynter,A., eta/. (2007) HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood, 110, 2140-2147. 

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

In the case of hyperphenylalaninaemia, which occurs ia phenylketonuria because of a congenital absence of phenylalanine hydroxylase, the observed phenylalanine inhibition of proteia synthesis may result from competition between T.-phenylalanine and L-methionine for methionyl-/RNA. Patients sufferiag from maple symp urine disease, an inborn lack of branched chain oxo acid decarboxylase, are mentally retarded unless the condition is treated early enough. It is possible that the high level of branched-chain amino acids inhibits uptake of L-tryptophan and L-tyrosiae iato the brain. Brain iajury of mice within ten days after thek bkth was reported as a result of hypodermic kijections of monosodium glutamate (MSG) (0.5—4 g/kg). However, the FDA concluded that MSG is a safe kigredient, because mice are bom with underdeveloped brains regardless of MSG kijections (106). 

Although essential amino acids are requited by both host and tumor, deprivation of select essential amino acids for 2—3 weeks is tolerated by the host yet exerts a pronounced antiproliferative effect on the tumor. Thus, treatment of mice with indole-3-alkane-a-hydroxylase [63363-76-8] from Pseudomonas, which transforms L-tryptophan [73-22-3] to 3-indolylglycaldehyde, lowers the concentration of L-tryptophan in plasma, brain, and lungs, and inhibits the growth of a variety of tumors (32—34). 

Catecholamine biosynthesis begins with the uptake of the amino acid tyrosine into the sympathetic neuronal cytoplasm, and conversion to DOPA by tyrosine hydroxylase. This enzyme is highly localized to the adrenal medulla, sympathetic nerves, and central adrenergic and dopaminergic nerves. Tyrosine hydroxylase activity is subject to feedback inhibition by its products DOPA, NE, and DA, and is the rate-limiting step in catecholamine synthesis the enzyme can be blocked by the competitive inhibitor a-methyl-/)-tyrosine (31). 

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