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Cytochrome P450 System (cytochrome + p450_system)
Selected AbstractsBench to Bedside: Pharmacogenomics, Adverse Drug Interactions, and the Cytochrome P450 SystemACADEMIC EMERGENCY MEDICINE, Issue 12 2005Rishi Sikka MD As physicians attempt to improve the quality of health care, one area of particular concern has been preventable medical errors from adverse drug interactions. The cytochrome P450 family of enzymes has been implicated in a large number of these preventable, adverse drug interactions. This report reviews the basic biochemistry and pharmacogenomics underlying the reactions catalyzed by the cytochrome P450 family of enzymes. An emphasis is placed on the phenotypic variations within a population and the resulting clinical effects. In addition, six members of the cytochrome P450 superfamily that are responsible for the metabolism of the majority of pharmaceutical agents are profiled in detail. These enzymes, CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2, are reviewed with regard to their phenotypic variation in the population and the resulting clinical and therapeutic implications. [source] Dose-dependent stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3,,4,4,-tetrachlorobiphenylENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2000Patrick M. Boyer Abstract Extremely low stores of vitamin A have been reported in fish and birds inhabiting regions contaminated by coplanar polychlorinated biphenyls (PCBs) and other organochlorines, suggesting many possible effects on retinoid biochemical pathways. Metabolic imbalances associated with biologically active retinoids (e.g., retinoic acid) could be associated with teratogenesis, edema, growth inhibition, reproductive impairment, immunosuppression, and susceptibility to cancer. Sexually mature brook trout were injected intraperitoneally with the coplanar PCB 3,3,,4,4,-tetrachlorobiphenyl (TCBP) and again 4 weeks later. At 8 weeks, retinoic acid metabolism was measured in liver microsomes. To our knowledge, retinoic acid conjugation by UDP-glucuronyltransferase is described here for the first time in fish. A substantial rate of glucuronidation was detected in the microsomes from control brook trout, which tended to increase over the dose range of TCBP. Glucuronidation was significantly greater in fish receiving the 10 ,g/g body weight dose level. Metabolism through the cytochrome P450 system was also dose-dependent, resulting in significantly greater production of 4-hydroxyretinoic acid at the 10 ,g/g dose level. In contrast, subsequent oxidation to 4- oxo -retinoic acid was greatest at the 1 ,g/g dose level and did not increase further at higher doses. Liver stores of dehydroretinyl palmitate/oleate were significantly decreased at the 5 and 10 ,g/g dose levels. [source] Mechanisms underlying the inhibition of the cytochrome P450 system by copper ionsJOURNAL OF APPLIED TOXICOLOGY, Issue 8 2009M. E. Letelier Abstract Copper toxicity has been associated to the capacity of free copper ions to catalyze the production of superoxide anion and hydroxyl radical, reactive species that modify the structure and/or function of biomolecules. In addition, nonspecific Cu2+ -binding to thiol enzymes, which modifies their catalytic activities, has been reported. Cytochrome P450 (CYP450) monooxygenase is a thiol protein that binds substrates in the first and limiting step of CYP450 system catalytic cycle, necessary for the metabolism of lipophilic xenobiotics. Therefore, copper ions have the potential to oxidize and bind to cysteinyl residues of this monooxygenase, altering the CYP450 system activity. To test this postulate, we studied the effect of Cu2+ alone and Cu2+/ascorbate in rat liver microsomes, to independently evaluate its nonspecific binding and its pro-oxidant effects, respectively. We assessed these effects on the absorbance spectrum of the monooxygenase, as a measure of structural damage, and p -nitroanisole O -demethylating activity of CYP450 system, as a marker of functional impairment. Data obtained indicate that Cu2+ could both oxidize and bind to some amino acid residues of the CYP450 monooxygenase but not to its heme group. The differences observed between the effects of Cu2+ and Cu2+/ascorbate show that both mechanisms are involved in the catalytic activity inhibition of CYP450 system by copper ions. The significance of these findings on the pharmacokinetics and pharmacodynamics of drugs is discussed. Copyright © 2009 John Wiley & Sons, Ltd. [source] Mechanism of inhibition of purified leaping mullet (liza saliens) NADPH-cytochrome P450 reductase by toxic metals: Aluminum and thalliumJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2007Azra Bozcaarmutlu Abstract Aluminum and thallium may reach life-threatening levels in aquatic systems in the near future because of their extensive use in various industrial fields. It is therefore important to study the mechanism of toxicity of aluminum and thallium on fish enzymes. To this aim, the effects of aluminum and thallium on the activity of purified leaping mullet (Liza saliens) cytochrome P450 reductase, an essential component of the important cytochrome P450 system, have been studied. Results indicated that both metal ions strongly inhibited the NADPH-cytochrome P450 reductase. The IC50 values of AlCl3 and TlCl3 were estimated to be 34 ,M and 3 ,M, respectively. The Lineweaver,Burk plot and Dixon plot revealed that both metal ions noncompetitively inhibited the purified mullet cytochrome P450 reductase. The Ki values of Al3+ and Tl3+ were calculated from Dixon plots as 8.9 and 5.6 ,M, respectively. The inhibitory effects of Al3+ and Tl3+ on purified cytochrome P450 reductase were partially recovered by 1 mM EDTA. Additionally, tin and magnesium were shown to have no apparent effect on purified mullet cytochrome P450 reductase. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:340,3347, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20200 [source] The pharmacology of cilostazolDIABETES OBESITY & METABOLISM, Issue 2002Karsten Schrör Cilostazol (6-[4-(1-cyclohexyl- 1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 µm). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration. [source] Modulation of hepatic cytochrome P450 during Listeria monocytogenes infection of the brainJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2003Elena Garcia Del Busto Cano Abstract Hepatic cytochrome P450 enzymes can be modulated during systemic infections. Inflammatory responses in the brain have also been shown to cause a significant decrease in the levels and activities of important cytochrome P450 isoforms in the liver. We determined some of the effects of central nervous system (CNS) Listeria monocytogenes infection on hepatic cytochrome P450 systems in rats. Intracerebroventricular injection of L. monocytogenes resulted in a time-dependent modulation of CYP1A, CYP2B, and CYP3A activities in the liver. Total hepatic cytochrome P450 content was significantly lowered 48 h after administration of the bacterium, and hepatic CYP1A and CYP2B activities were significantly altered 48 and 72 h after infection, respectively, whereas CYP3A activity and protein content were depressed 72 h after the insult. Bacterial load in the brain increased dramatically over a 72-h period, but the number of bacteria cultured from liver over this time period was relatively small. Therefore, an infection largely confined to the CNS in the rat results in abnormal activity levels of certain hepatic cytochrome P450 enzymes crucial in drug metabolism. If such a response also occurs in humans, this has the potential to produce serious complications with drug and endogenous substrate metabolism in patients with an infectious disease involving the CNS. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1860,1868, 2003 [source] | |||||||||||||