Hepatic microsomes

Servent, D., Delaforge, M., Ducrocq, C., Mansuy, D., Lenfant, M., Nitric oxide formation during microsomal hepatic denitration of glyceryl trinitrate involvement of cytochrome P-450. Biochem. Biophys. Res. Commun. 163 (1989),... 

Clearance of antipyrine, a known substrate for microsomal hepatic enzymes, was used to test liver function in two studies of PCB-exposed workers (Alvares et al. 1977 Emmett et al. 1988b). A significantly lower mean half-life of antipyrine clearance from blood was found in five workers exposed... 

Low metabolic Microsome (hepatic, intestinal) or Reduce lipophilicity, block... 

Intestinal absorption of digoxin is less complete compared to digitoxin. In order to improve absorption, acetylated- and methylated-digoxin derivates were developed. Digitoxin is metabolised in hepatic microsomal enzymes and can be cleared independently from renal function. The therapeutical serum level of digoxin is 0.5-2.0 ng/ml and 10-35 ng/ml of digitoxin. Steady state plateau of therapeutic plasma concentrations is reached after 4-5 half-life-times using standard daily doses [5]. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Cimetidine, an H2 antagonist used therapeutically in patients with ulcers, inhibits activity of hepatic microsomal enzymes. When rats or mice were pretreated with cimetidine, dose-related lethality of methyl parathion was reduced, and cholinergic signs of toxicity were delayed. Simultaneous administration with methyl parathion did not reduce toxicity (Joshi and Thornburg 1986). 

Evidence suggests that endosulfan can induce microsomal enzyme activity. Increased liver microsomal cytochrome P-450 activity was observed in male and female rats after single and multiple administrations of endosulfan (Siddiqui et al. 1987a Tyagi et al. 1984). Increased enzyme activity was observed in hepatic and extrahepatic tissues. Based on the increase in aminopyrine-A-demethylase and aniline hydroxylase activity, endosulfan has been shown to be a nonspecific inducer of drug metabolism (Agarwal et al. 1978). 

FIGURE 2.8 Monooxygenase activities of mammals, birds, and fish, (a) Mammals and birds, (b) Mammals, birds, and fish. Activities are of hepatic microsomal monooxygenases to a range of substrates expressed in relation to body weight. Each point represents one species (males and females are sometimes entered separately) (from Walker et al. 2000). 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

Under anaerobic conditions, p,p -DDT is converted to p,p -DDD by reductive dechlorination, a biotransfonnation that occurs postmortem in vertebrate tissues such as liver and muscle and in certain anaerobic microorganisms (Walker and Jefferies 1978). Reductive dechlorination is carried out by reduced iron porphyrins. It is carried out by cytochrome P450 of vertebrate liver microsomes when supplied with NADPH in the absence of oxygen (Walker 1969 Walker and Jefferies 1978). Reductive dechlorination by hepatic microsomal cytochrome P450 can account for the relatively rapid conversion of p,p -DDT to p,p -DDD in avian liver immediately after death, and mirrors the reductive dechlorination of other organochlorine substrates (e.g., CCI4 and halothane) under anaerobic conditions. It is uncertain to what extent, if at all, the reductive dechlorination of DDT occurs in vivo in vertebrates (Walker 1974). 

The anticoagulant rodenticides warfarin and superwarfarins are toxic because they have high affinity for a vitamin K binding site of hepatic microsomes (Chapter 11, Section 11.2.4). In theory, an ideal biomarker would... 

Endoplasmic reticulum Membranous network of cells that contains many enzymes that metabolize xenobiotics. Hepatic microsomes consist mainly of vesicles derived from the endoplasmic reticulum of liver. 

Microsomes Vesicles obtained from homogenized tissues by ultracentrifugation. They are derived mainly from the endoplasmic reticulum in the case of the liver (hepatic microsomes). 

Fent, K. and Bucheli, T.D. (1994). Inhibitors of hepatic microsomal monooxygenase system by organotins in vitro in freshwater fish. Aquatic Toxicology 28, 107-126. 

Hosokawa, M., Maki, T., and Satoh, T. (1987). Mnltiphcity and regnlation of hepatic microsomal carboxylesterases in rats. Molecular Pharmacology 31, 579-584. 

Walker, C.H. (1980). Species variations in some hepatic microsomal enzymes that metabolise xenobiotics. Progress in Drug Metabolism 5, 118-164. 

Hoen P.A. C., Prince P., Van der Bilt E., Valentijn A. R., Meeuwenoord N.J., Princen H., Bijsterbosch M.K., van der Marel G.A., van Boom J.H., van BerkelT.J.C. Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepato-cytes. Bioconjug. Chem. 2002 13 295-302. 

Houston JB, Carlile DJ. Prediction of hepatic clearance from microsomes, hepa-tocytes, and liver slices. Drug Metab Rev 1997 Nov 29(4) 891-922. 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

The cytochrome P-450-dependent metabolism of trichloroethylene was studied in hepatic microsomal fractions from 23 different humans (Lipscomb et al. 1997). CYP2E1 was the predominant form of P-450 responsible for the metabolism of trichloroethylene in humans. Incubations of trichloroethylene with the microsomal preparations resulted in hyperbolic plots consistent with Michaelis-Menton kinetics. The values ranged from 12 to 55.7 pM, and were not normally distributed, and the values range from 490 to 3,455 pmol/min/mg protein and were normally distributed. The study authors concluded that the human variability in metabolism of trichloroethylene via P-450-dependent pathways was within a 10-fold range. 

Costa AK, Katz ID, Ivanetich KM. 1980. Trichloroethylene Its interaction with hepatic microsomal cytochrome P-450 in vitro. Biochem Pharmacol 29 433-439. 

CHOI J H, CHA B K and RHEE s J (1998) Effects of green tea catechin on hepatic microsomal phospholipase A2 activities and changes of hepatic phospholipid species in streptozotocin-induced diabetic rats , JNutr Sci Vitaminol (Tokyo), 44 (5), 673-83. 

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