Microsomes inhibition

CYP2C8 has recently been established at the principal enzyme responsible for the 6a-hydroxylation of taxol, the principal route of metabolism for this anticancer drug (Rahman et al., 1994). For this study, a combined approach of correlation analysis with levels of immunoquantitated CYP2C8 protein in human liver microsomes, inhibition analyses in human liver microsomes, and vv-expressed proteins established that CYP2C8 was the principal enzyme for taxol 6a-hydroxylation and that this enzyme catalysed the reaction at high turnover (30/min). 

Protection of vascular endothelial cells from oxygen free radical damages Enhancement of SOD, catalase and peroxidase in the cytosol of kidney Protection of pulmonary endothelium against free radicals in rabbits Protection of lipid peroxidation in liver and cardiac muscle in rats Inhibition of lipid peroxidation of rat liver and brain microsomes Inhibition of lipid peroxidation in serum and liver in rats Protective effect of ginsenosides on reperfusion injuries... 

Belpaire FM, Wijnant P, Temmerman A, et al. The oxidative metabolism of metoprolol in human liver microsomes-inhibition by the selective serotonin reuptake inhibitors. Eur J Clin Pharmacol 1998 54 261-264. 

Sreejayan N, Rao MNA, Priyadarsini Kl, Devasagayam TPA. (1997) Hydroxyl radical induced Kpid peroxidation in rat liver microsomes Inhibition by curcumin. Int JPharm 151 127-130. 

Tjia, J.F. Colbert, J. Back, D.J. Theophylline metaholism in human liver microsomes Inhibition studies. J.Pharmacol.Exp.Ther., 1996, 276, 912—917... 

Rat Liver microsomes Inhibition of DMN demethylase by N (2-chloroethyl)dibenzylamine (di-benamine) 445... 

Pinot F, Borsch H, Mioskowski C, Durst F, Salaiin JP. (O-hydroxylation of oleic acid in Vida sativa microsomes inhibition by substrate analogues and inactivation by terminal acetylenes. Plant Physiol 1994 000-000. 

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

In recent in vitro studies, an aromatase inhibiting effect on human placental microsomal extracts has been demonstrated with both tributyltin chloride and dibutyltin dichloride (Heidrich et al, 2001 Cooke,... 

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). 

Piperonyl butoxide, a common potentiator of insecticide effects that inhibits microsomal enzymes, antagonized the toxic effects of methyl parathion in mice (Mirer et al. 1977). 

Kitada, M., Igarashi, K., Hirose, S. Kitagawa, H. (1979). Inhibition by polyamines of lipid peroxide formation in rat liver microsomes. Biochemical Biophysical Research Communications, 87, 388-92. 

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. 

Lewis DF, Lake BG, Bird MG. Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 A resolution structure-activity relationships in epoxides inhibiting EH activity. Toxicol In Vitro 2005 19 517-22. 

Figure 11-5. Electron transport chain in microsomes. Cyanide (CN ) inhibits the indicated step.

Figure 11-6. Cytochrome P450 hydroxylase cycle in microsomes. The system shown is typical of steroid hydroxylases of the adrenal cortex. Liver microsomal cytochrome P450 hydroxylase does not require the iron-sulfur protein FejSj. Carbon monoxide (CO) inhibits the indicated step.

Figure 23-3. Biosynthesis of the co9, co6,and co3 families of polyunsaturated fatty acids. Each step is catalyzed by the microsomal chain elongation or desaturase system 1,elongase 2,A desaturase 3,A desaturase 4,A desaturase. ( .Inhibition.)...

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

Polyphenols and flavanoids in rat liver microsomal fractions have been demonstrated to inhibit glucuronidation of estrone and estradiol in vitro (Zhu et al, 1998). In addition, flavonoids have also been found to induce phase I and II enzymes in rats including UDP-glucuronosyl transferase (Seiss et al, 1996). However, the effects of phytoestrogens have not been evaluated for either their inhibition or induction of glucuronosyl transferase activity. 

Anti-mutagenic and anti-carcinogenic effect elevation of phase II microsomal enzymes and inhibition of phase 1 enzymes (Manorama, 1993). 

Tocotrienols present in rice bran inhibit the liver microsomal enzyme HMGCoA reductase (Qureshi and Qureshi, 1992), the key enzyme involved in the endogenous synthesis of cholesterol, and this helps to lower the circulating cholesterol. Inhibition of another enzyme, ACAT (Acyl coenzyme A acyl transferase), by y-oryzanol results in lowered LDL-C synthesis and enrichment... 

---