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Cytochrome P450 Isoforms (cytochrome + p450_isoform)
Selected AbstractsInhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifosJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2007Hyun Joo Abstract Previous studies have established that chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by human liver microsomes (HLM) and a number of cytochrome P450 (CYP) isoforms. However, metabolic interactions between these three substrates have not been described. In this study the effect of either coincubation or preincubation of CPS with HLM or CYP isoforms with either fipronil or nonane as substrate was investigated. In both co- and preincubation experiments, CPS significantly inhibited the metabolism of fipronil or nonane by HLM although CPS inhibited the metabolism of fipronil more effectively than that of nonane. CPS significantly inhibited the metabolism of fipronil by CYP3A4 as well as the metabolism of nonane by CYP2B6. In both cases, preincubation with CPS caused greater inhibition than coincubation, suggesting that the inhibition is mechanism based. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:76,80, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20161 [source] Quantification of the expression and inducibility of 12 rat cytochrome P450 isoforms by quantitative RT,PCRJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2006Etienne Caron Abstract The administration of xenobiotics may significantly alter the expression of cytochromes P450 (CYPs), thereby leading to potentially toxic cellular, physiologic, and pharmacologic responses. Indeed, an important task in the development of new therapeutic entities is to evaluate efficiently and quantitatively their potential effects on the expression level of different CYPs. In this report, reverse transcriptase polymerase chain reaction (RT,PCR) was used to measure basal and induced mRNA of a wide range of rat CYP isoforms. Rats (n = 3 per treatment) were treated with five prototype inducers of CYP isoforms or with vehicle only. RT and PCR efficiencies were determined using appropriate RNA and DNA standards. Messenger RNA was quantified by PicoGreen standard curves and normalized to cyclophilin. Quantitative RT,PCR was used successfully to demonstrate that CYP isoforms were induced at the mRNA level following drug administration. Notably, phenobarbital resulted in significant induction of CYP2B1, CYP2B2, CYP2C6, CYP2C13, CYP2E1, CYP3A1, and CYP3A2. 3-Methylcholanthrene induced CYP1A1, CYP1A2, and CYP1B1. CYP2C11 expression was highly variable and suppressed by pyridine, whereas the expression of CYP2E1 was suppressed by dexamethasone. We demonstrated that quantitative RT,PCR can be used to evaluate efficiently the effect of compounds on the expression of a wide range of CYP isoforms. The technique is advantageous over others in that it is very sensitive, efficient and applicable to highly homologous CYP isoforms. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:368,378, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20103 [source] Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytesJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 3 2005Pavel Kosina Abstract Four ,-glycosides of flavonoligan silybin, i.e. silybin ,-galactoside, silybin ,-glucoside, silybin ,-maltoside, silybin ,-lactoside were synthesized in order to improve silybin water solubility and bioavailability (K,en et al., J Chem Soc, Perkin Trans 1, 2467,2474, 1997). The presented paper deals with the effect of silybin and its synthetic ,-glycosides on the expression of two major cytochrome P450 isoforms, CYP1A2 and CYP3A4. Primary cultures of human hepatocytes were the model of choice. mRNAs were analyzed using Northern blot and P-radiolabelled probes. CYP protein content was determined by immunoblotting using specific antibodies. Silybin and its ,-glycosides do not induce expression of CYP1A2 and CYP3A4. Tested compounds did not affect inducible expression of CYP1A2 and CYP3A4 by dioxin and rifampicin, respectively, as evaluated at the level of mRNAs and proteins. Silybin and its ,-glycosides do not interfere with the expression of CYP1A2 and CYP3A4, are not likely to produce drug,drug interactions in terms of the inducibility of two important cytochromes P450. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:149,153, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20066 [source] Inhibition of human cytochrome P450 isoforms and NADPH-CYP reductase in vitro by 15 herbal medicines, including Epimedii herbaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2006K. H. Liu PhD Summary Objective:, We evaluated the potential of 15 herbal medicines (HMs), commonly used in Korea, to inhibit the catalytic activities of several cytochrome P450 (CYP) isoforms and microsomal NADPH-CYP reductase. Methods:, The abilities of 1,1000 ,g/mL of freeze-dried aqueous extracts of 15 HMs to inhibit phenacetin O -deethylation (CYP1A2), tolbutamide 4-methylhydroxylation (CYP2C9), S -mephenytoin 4,-hydroxylation (CYP2C19), dextromethorphan O -demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), midazolam 1-hydroxylation (CYP3A4) and NADPH-CYP reductase were tested using human liver microsomes. Results:, The HMs Epimedii herba, Glycyrrhizae radix and Leonuri herba inhibited one or more of the CYP isoforms or NADPH-CYP reductase. Of the three HMs, Epimedii herba extracts were the most potent inhibitors of several CYP isoforms (IC50 67·5 ,g/mL for CYP2C19, 104·8 ,g/mL for CYP2E1, 110·9 ,g/mL for CYP2C9, 121·9 ,g/mL for CYP3A4, 157·8 ,g/mL for CYP2D6 and 168·7 ,g/mL for CYP1A2) and NADPH-CYP reductase (IC50 185·9 ,g/mL). Conclusion:, These results suggest that some of the HMs used in Korea have the potential to inhibit CYP isoforms in vitro. Although the plasma concentrations of the active constituents of the HMs were not determined, some herbs could cause clinically significant interactions because the usual doses of those individual herbs are several grams of freeze-dried extracts. Controlled trials to test the significance of these results are necessary. [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] | ||||||||||