Hepatic microsomal electron

Scheme 1. Hepatic microsomal electron transport for drug oxidation and...

J. Aranda, S. MacLeod, K. Renton, and N. Eade, Hepatic microsomal drug oxidation and electron transport in newborn infants, J. Pediatr, 85, 534 (1974). 

Nitrobenzyl chlorides are also reduced by microsomes through one-electron reduction mechanism. Moreno et al. [47] suggested that p- and o-nitrobenzyl chlorides are reduced by rat hepatic microsomes to unstable radical anions, which are decomposed to form benzyl radicals under anaerobic conditions. However, in the presence of dioxygen the radical anions of these compounds participate in futile redox cycling yielding superoxide (Figure 24.2). In contrast to p- and o-nitrobenzyl chlorides, m-nitrobenzyl chloride was reduced by microsomes to a relatively stable m-nitrobenzyl radical anion. 

Pawar SS, Kachole MS. 1978. Hepatic and renal microsomal electron transport reactions in endrin treated female guinea pigs. Bull Environ Contam Toxicol 20 199-205. 

Electron paramagnetic resonance (EPR) examination of hepatic microsomes from differently pretreated animals has lead to the conclusion that MC pretreatment leads to the formation of cytochrome P-1+50 (P-1+1+8) with high spin iron (6, 1+6). Chevion et al. (28) failed to demonstrate the presence of high spin cytochrome P-1+50 in a teleost fish even after induction with MC. The work of Chevion et al. (28 ) indicates further that the fish cytochrome P-1+50, which is inducible with PAH s and metabolizes readily PAH s, is not identical with the mammalian cytochrome P-1+1+8. 

Chevion, M., Stegeman, J.J., Peisach, J. and Blumberg, W.E. Electron paramagnetic resonance studies on hepatic microsomal cytochrome P- 50 from a marine teleost fish. Life Sci. (1977) 20, 895-900. 

Further support for electron abstraction from nitrogen is derived from experiments on 1,4 dihydropyridine 138 with hepatic microsomes [96]. In the course of the incubation significant deactivation of the P450 enzyme was observed suggesting heme alkylation. Subsequent isolation and characterization of N-ethylprotoporphyrin IX indicated an ethyl radical transfer from the... 

Aldehydes - The destruction of cytochrome P-A50 by aromatic aldehydes is accompanied by equimolar loss of microsomal heme. > Aliphatic aldehydes also destroy cytochrome P-450 but, unlike the aromatic analogues, only appear to be active in vitro.Enzyme destruction by these monoaldehydes is distinguished from that mediated by phthalaldehyde by a requirement for NADPH. The incubation of octanal with hepatic microsomes from rats pretreated with radiolabeled levulinic acid to tag the heme groups causes the formation of a radiolabeled "green" pigment, but the electronic spectrum of the pigment lacks the features that characterize N-alkylprotoporphyrin IX derivatives. ... 

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to a reduction in hepatic microsomal protein and lipid deficiency oxidative metabolism is decreased because of an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body. 

Soni M, Nomiyama H, Nomiyama K. 1990. Chronic inhalation effects of tetrachloroethylene on hepatic and renal microsomal electron transport components and 6-aminolevulinic acid dehydratase in rats. Toxicology Letters 54 207-213. 

Manno et al. [43] observed the formation of superoxide during the oxidation of arylamines by rat liver microsomes. Noda et al. [44] demonstrated that microsomes are able to oxidize hydrazine into a free radical. In contrast, hepatic cytochrome P-450 apparently oxidizes paracetamol (4 -hydroxyacetanilide) to A-acetyl-p-benzoquinone imine by a two-electron mechanism [45]. Younes [46] proposed that superoxide mediated the microsomal S -oxidation of thiobenzamide. 

Dihaloelimination is a two-electron transfer reaction. Thompson et al. [377] reported reductive dichloroelimination of 1,1,2-TCA and TeCA by hepatic micro-somes from rat Ever, with VC and both tDCE and cDCE as metabolites. Reductive dichloroelimination from hexa- and pentachloroethane by microsomal cytochrome P450 was studied by Nastainczyk et al. [378]. The main products of the in vitro metabolism of hexa- and pentachloroethane were PCE (99.5%) and TCE (96%), respectively, with minor amounts of pentachloroethane (0.5%) and TeCA (4%), respectively, via reductive dechlorination. 

The hepatic effects of cinnamyl anthranilate were evaluated in male CD 1 mice and male Fischer 344 rats treated by intraperitoneal injection for three consecutive days (Viswalingam Caldwell, 1997). At doses of 100 and 1000 mg/kg bw per day, relative liver weights of mice increased by 22% and 50%, respectively, 24 h after the final dose and peroxisomal (cyanide-insensitive) palmitoyl-coenzyme A (CoA) oxidation activity increased fivefold at both levels. Microsomal lauric acid 11- and 12-hydroxylase activity (CYP4A) was increased 15-fold at 100 mg/kg bw per day and 17-fold at 1000 mg/kg bw per day. Limited evaluation indicated that cirmamyl anthmilate increased the size and number of peroxisomes in electron micrographs of hepatocytes of treated mice. In rats, relative liver weights and peroxisomal palmitoyl-CoA oxidation activity were significantly increased only at 1000 mg/kg bw per day (22% and twofold, respectively). 

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... 

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