Bile acids activation enzyme

Based on the results reported above, it was suggested that the microsomes are bearcra of the bile acid activating enzyme system and the lysosomes or perhaps the peroxisomes are bearers of the enzyme or enzymes that catalyze the transference of the bile-acyl group from bile-acyl-iS-CoA to taurine and glycine, e.g., according to Bremer (1956c) the bile acyl transferase I and the bile acyl transferase II. 

Micromolar quantities of RNS are generated primarily by nitric oxide synthase 2 (NOS2), an enzyme that is up-regulated during colon-cancer progression. As discussed below, deoxycholate (DOC), a hydrophobic secondary bile acid, activates the redox-sensitive transcription factor NF-kB, resulting in increased levels of NOS2 and enhanced S-nitrosylation of proteins. Additional sources of bile-acid-induced ROS and RNS are also likely. ... 

Taken together, FXR not only regulates bile acid homeostasis but also greatly impacts on transporters and enzymes involved in drug metabolism. Effects on phase I—III genes by bile acid-activated FXR may therefore at least in part explain alterations of drug metabolism in cholestatic liver disease [62, 85, 86]. 

Lack of, or injury to, conjugating enzymes—either bile acid-activating or bile acyl-transferring, or both... 

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

The most common assay uses 3a-hydroxysteroid dehydrogenase to form the 3-keto bile acid that is trapped by, for example, hydrazine hydrate, causing the reaction to go to completion. The co-factor NAD is reduced stoichiometrically and can be measured by ultraviolet absorption or more commonly by fluorescence at an activation of 345 nm and emission of 450 nm. Use of this enzyme measures all bile acids with a 3a-hydroxyl but not cholesterol, which has a 3p-hydroxyl, and does not measure bile acids with a sulphate or glucuronide group conjugated to the 3a-hydroxyl. 

Utilising a reversion assay in Salmonella enterica, Prieto et al reported an increased frequency of point mutations following bile-salt exposure. Mutations were predominantly nucleotide substitutions (GC to AT transitions) and -1 frameshift mutations.The frameshifts were dependent on SOS induction and linked to the activity of DinB polymerase (Pol IV). The authors proposed that the GC to AT transitions stimulated by bile, could have arisen from oxidative processes giving rise to oxidised cytosine residues. Consistent with this hypothesis, the authors demonstrated that strains of S. enterica-lacking enzymes required for base-excision repair (endonuclease III and exonuclease IV) and the removal of oxidised bases, demonstrated increased bile-acid sensitivity compared with competent strains. In another study using E. coli, resistance to the DNA-damaging effects of bile was associated with Dam-directed mismatch repair, a pathway also involved with the repair of oxidative DNA lesions. ... 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

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