Aminotransferases inhibition

Alanine aminotransferase inhibition. Decoction of dried rhizome, taken orally by human adults of both sexes at a dose of 7.5 g/day for 6 months, was active on 80 patients with hepatitis B antigen-positive chronic hepatitis. The study was conducted with a prescription that consists of B.upku-rum falcatum Bupleurum falcatum (Rt), Scutellaria baicalensis Scutellaria baicalensis (Rt), Pinellia ternata (Tu), Zizyphus jujuba (Fr), Panax ginseng (Rt), and Glycyrrhiza glabra (Rh) . 

Product inhibition is a cause of nonlinearity of reaction progress curves during fixed-time methods of enzyme assay. For example, oxaloacetate produced by the action of aspartate aminotransferase inhibits the enzyme, particularly the mitochondrial isoenzyme. The inhibitory product may be removed as it is formed by a coupled enzymatic reaction malate dehydrogenase converts the oxaloacetate to malate and at the same time oxidizes NADH to NADL... 

Another class of therapeutic agents is used for the treatment of certain genetic diseases or other enzymatic disorders caused by the dysfunction or absence of one particular enzyme. This often leads to an unwanted accumulation or imbalance of metaboUtes in the organism. Eor example, some anticonvulsive agents are inhibitors for y-aminobutyric acid aminotransferase [9037-67-6]. An imbalance of two neurotransmitters, glutamate and y-aminobutyric acid, is responsible for the symptoms. Inhibition of the enzyme leads to an increase of its substrate y-aminobutyric acid, decreasing the imbalance and subsequently relieving the symptoms of the disease. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Use of zileuton is limited due to the potential for elevated hepatic enzymes (especially in the first 3 months of therapy), and inhibition of the metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline, warfarin). Serum alanine aminotransferase should be monitored before treatment and then periodically thereafter. 

Adverse effects that are not unequivocally related to inhibition of prostaglandin synthesis include hepatic effects (hepatitis, hepatic necrosis, cholestatic jaundice, increased serum aminotransferases), dermal effects (photosensitivities, Stevens-Johnson syndrome, toxic epidermal necrolysis, onycholysis), central nervous system (CNS) effects (headaches, dizziness, tinnitus, deafness, drowsiness, confusion, nervousness, increased sweating, aseptic meningitis), ocular effects (toxic amblyopia, retinal disturbances), and certain renal effects (acute interstitial nephritis, acute papillary necrosis). 

Complexity of inhibition of PLP-dependent enzymes is highlighted by detailed investigations on the inhibition of y-aminobutyric acid aminotransferase (GABA-AT), the enzyme responsible for the degradation of y-aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the mammalian central nervous system. Inhibition of GAB A-AT results in an increased concentration of GABA in the brain and could have therapeutic applications in neurological disorders (epilepsy, Parkinson disease, and Alzheimer disease). 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

Salicylate also inhibits aminotransferases, leading to increased amino acid levels in blood and aminoaciduria. This also increases the solute load and contributes to the dehydration. 

PLP-dependent enzymes are inhibited by a great variety of enzyme-activated inhibitors that react by several distinctly different chemical mechanisms.11 Here are a few. The naturally occurring gabaculline mimics y-aminobutyrate (Gaba) and inhibits y-aminobutyrate aminotransferase as well as other PLP-dependent enzymes. The inhibitor follows the normal catalytic pathway as far as the ketimine. There, a proton is lost from the inhibitor permitting formation of a stable benzene ring and leaving the inhibitor stuck in the active site ... 

A cycloglutamate that inhibits An isomeric cycloglutamate tricholomic aspartate aminotransferase acid found in certain mushrooms... 

Soyasaponin I (1) inhibited the elevation of aspartate aminotransferase (AST) activity, which was comparable to that of glycyrrhizin (positive control). On the other hand, Kaikasaponin HI (21) was more effective than 1. Compound 21 showed antihepatotoxic activity at less than 100p.g/ml. Furthermore, the highest activity was observed even at lower doses (50, 100pg/ml). Therefore, sophoradiol OGs were concluded to be the anti-hepatotoxic principle in both crude drugs (Abri Heba and Puerariae Flos). 

Enzymes containing pyridoxal phosphate are prime targets for suicide inhibition because the chemistry is so naturally suitable. As discussed in Chapter 2, section C2, the pyridoxal ring acts as an electron sink that facilitates the formation of carbanions and also forms part of an extended system of conjugated double bonds. For example, vinyl glycine, CH2=CHCH(NH3+)C02, condenses with the pyridoxal phosphate of aspartate aminotransferase to form a Schiff base, as described in Chapter 2, equation 2.42.19 The a proton may be abstracted (as in equation 2.43) so that the isomerization shown in equation 9.13 readily occurs. 

The intermediate 9.14 is probably generated during the suicide inhibition of /3-aspartate decarboxylase,21 aspartate aminotransferase,22 and alanine racemase23,24 by /3-chloroalanine. These enzymes are inactivated by the intermediate, since they have not evolved to cope with it during the normal course of reaction. 

Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in thalamic neurons. The T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack. Inhibition of this current could therefore account for the specific therapeutic action of ethosuximide. Ethosuximide also inhibits Na+/K+ ATPase, depresses the cerebral metabolic rate, and inhibits GABA aminotransferase. However, none of these actions are seen at therapeutic concentrations. 

Because the sulfide may be reoxidized to the inactive prodrug in the kidney, sulindac may inhibit renal COX less than other NSAIDs, though reversible renal failure and nephrotic syndrome have been observed with this drug. Among the more severe reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. Like diclofenac, sulindac may have some propensity to cause elevation of serum aminotransferases it is also sometimes associated with cholestatic liver damage, which disappears or becomes quiescent when the drug is stopped. 

The hepatotoxicity produced by acute carbon tetrachloride-induced liver injury was found to be inhibited by essential oil from fennel, as evidenced by decreased levels of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin (Ozbek et al., 2003). 

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