The microsomal cytochrome

Hereditary methemoglobinemia is classified into three types a red blood cell type (type I), a generalized type (type II), and a blood cell type (type HI). Enzyme deficiency of type I is limited to red blood cells, and these patients show only the diffuse, persistent, slate-gray cyanosis not associated with cardiac or pulmonary disease. In type II, the enzyme deficiency occurs in all cells, and patients of this type have a severe neurological disorder with mental retardation that predisposes them to early death. Patients with type III show symptoms similar to those of patients with type I. The precise nature of type III is not clear, but decreased enzyme activity is observed in all cells (M9). It is considered that uncomplicated hereditary methemoglobinemia without neurological involvement arises from a defect limited to the soluble cytochrome b5 reductase and that a combined deficiency of both the cytosolic and the microsomal cytochrome b5 reductase occurs in subjects with mental retardation. Up to now, three missense mutations in type I and three missense mutations, two nonsense mutations, two in-frame 3-bp deletions, and one splicing mutation in type n have been identified (M3, M8, M31). 

Superoxide generation was detected via the NADPH-dependent SOD-inhibitable epinephrine oxidation and spin trapping [15,16], Grover and Piette [17] proposed that superoxide is produced equally by both FAD and FMN of cytochrome P-450 reductase. However, from comparison of the reduction potentials of FAD (-328 mV) and FMN (190 mV) one might expect FAD to be the most efficient superoxide producer. Recently, the importance of the microsomal cytochrome h558 reductase-catalyzed superoxide production has been shown in bovine cardiac myocytes [18]. 

It is interesting to note that the outer mithocondrial membrane cytochrome b5, which is isostructural with the microsomal cytochrome b5,16 reduces, under the same experimental conditions, at slightly more negative potential values (E° = —0.05 V vs. NHE),17 suggesting the presence of minor structural differences. 

The most important group of liver enzymes that are responsible for the oxidative metabolism of most drugs are the microsomal cytochrome P450 oxidases. There are many subtypes (termed isozymes). 

Metabolism -The main route of argatroban metabolism is in the liver by the microsomal cytochrome P450 enzymes CYP3A4/5. Data suggest that CYP3A4/5 mediated metabolism is not an important elimination pathway in vivo. 

The microsomal cytochrome P-A50 system In the midguts of southern armyworm larvae oxidises pulegone vitro. The two major products, 9-hydroxypulegone and 10-hydroxypulegone are formed by mlcrosomes from larvae Induced with either pentamethylben-zene or a-plnene. Mlcrosomes from control (un-lnduced) larvae only oxidise trace amounts of the compound. The 9-hydroxypulegone rearranges spontaneously to menthofuran (38). 

Table VII shows the Increase In cytochrome P-450 content In mlcrosomes from southern armyworm larval midguts resulting from dietary exposure to several cyclic monoterpenes ( ). It also shows a closely corresponding Increase In the rate of NADPH oxidation when pyrethrum Is the substrate (R) being oxidised. The microsomal cytochrome P-450 system Is arranged as outlined In Figure 6, consisting of a terminal heme-lron protein that In the oxidised (Fe3+) state binds the substrate (R). The complex undergoes two reductions during which bound molecular oxygen Is converted to free radical species, one of which Is Inserted In the substrate molecule, and the other one forms water. The reductions...

Macrolides are metabolized in the liver via the microsomal (cytochrome P450) enzyme system. The alkylxanthines (e.g. theophylline, amino-phylline) utilize the same enzyme system, so concurrent administration with macrolides leads to a doubling of the alkylxanthine concentration and toxicity. Because of similar mechanisms of action, concurrent administration of other macrolides, lincosamides, chloramphenicol or florfenicol is not recommended. 

We used DEAE-cellulose gel column chromatography at subzero temperature in an ethylene glycol—water mixture to isolate the microsomal cytochrome P-450 in its stable form. The already known stabilizing effect of ethylene glycol and low temperature contribute to the stabilization of the enzyme. The preparation of rat liver microsomes and the assays were carried out as described earlier. The amount of phospholipid was measured by the method of Ames and Dubin (1960). 

Fig. 7 Catalytic cycle of the microsomal cytochrome P,/cytochrome I), system that is...

The turnover numbers found for 26-hydroxylation in the reconstituted system were 50-200 times higher than those reported for reconstituted systems from microsomes and it was concluded that the mitochondrial cytochrome P-450 has a much higher potential for 26-hydroxylation than the microsomal cytochrome P-450 [133]. 

Because phenobarbital induces the microsomal cytochrome P-450 enzyme system responsible for MBOCA hydroxylation (Chen et al. 1991), phenobarbital treatment might increase the breakdown of MBOCA and speed its removal from the body. However, because MBOCA s metabolites are more toxic than the unmetabolized moiety, this intervention must be used with caution. Such treatment could also affect MBOCA adduct formation. While phenobarbital did not increase in wVo hemoglobin adduct formation in one study in rats (Chen et al. 1991), Cheever et al. (1991) found an increase in... 

Acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) is a widely used over-the-counter analgesic. At erapeutic doses it is a safe drug. However, at high doses it may produce severe hepatic necrosis and has also been reported in some individuals to be nephrotoxic (1-3). Available evidence indicates that acetaminophen hepatotoxicity is not a result of the parent compound but is mediated by a reactive metabolite N-acetyl-g-benzoquinone imine (NAPQI). This metabolite is the two-electron oxidation product of acetaminophen and is formed by the microsomal cytochrome P-450 mixed function oxidase system (4-8). Following a therapeutic dose of acetaminophen the reactive metabolite is detoxified Current address National Institutes of Health, Bethesda, MD 20892 Current address Rohm and Haas Company, Spring House, PA 19477... 

Catechol estrogens 2-hydroxylated derivatives of estrogens. Estrogens are hydroxylated by the microsomal cytochrome P450 system of the liver. The 2-hy-droxyl group is then methylated by the action of me-thyitransferase and 5-adenosyl-L-methionine in the liver cytosol. The methoxy derivatives are excreted in the urine. Ce. and their methylated derivatives... 

Davydov R, Razeghilard R, Im SC, Waskell L, Hoffman BM (2008) Characterization of the microsomal cytochrome P450 2B4 Oj activation intermediates by cryoreduction and electron paramagnetic resonance. Biochemistry 47 9661 9666... 

Physiologically, microsomal oxidation via the cytochromes appears to serve for the lipophilic oxidation of steroids, fatty acids, heme, and drugs. The microsomal cytochromes and smooth endoplasmic reticulum may be controlled in part by steroids. For example, the relatively high production of heme by normal liver suggests that there may be natural 5/i-H steroids that normally serve to maintain a certain rate of heme synthesis by inducing the synthesis of ALA-synthetase. An... 

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