Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three new sesquiterpenes, (2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (1), (2R,3R,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (2), and (5R)-2,6,9-humulatrien-5-ol-8-one (3), and two new flavonol glycosides, kaempferol-3-O-(2,3-di-O-acetyl-alpha-l-rhamnopyranoside) (4) and kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5), were isolated from the EtOAc-soluble fraction of the water extract of Zingiber aromaticum, along with 13 known compounds (6-18). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5) showed the most potent inhibitory activity (IC(50), 14.4 microM) on the metabolism mediated by CYP3A4, and kaempferol-3-O-methyl ether (14) inhibited CYP2D6 most potently (IC(50), 4.63 microM).
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PMID:Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities. 1527 May 56

Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude.
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PMID:CYP3A variation and the evolution of salt-sensitivity variants. 1549 26

A rapid and sensitive radiometric assay for assessing the potential of drugs to inhibit cytochrome P450 (P450) 3A4/5 in human liver microsomes is described. In contrast to the conventional testosterone 6beta-hydroxylation assay, the new method does not require high-performance liquid chromatography (HPLC) separation and mass spectrometry. The assay is based on the release of tritium as tritiated water that occurs upon CYP3A4/5-mediated 6beta-hydroxylation of testosterone labeled with tritium in the 6beta position. The radiolabeled product is separated from the substrate using 96-well solid-phase extraction plates. Using commercially available [1,2,6,7-(3)H]testosterone as substrate, we demonstrated that the reaction is NADPH-dependent, and sensitive to CYP3A4/5/5 inhibitors and a CYP3A4/5/5-specific inhibitory monoclonal antibody, but not to inhibitors of or antibodies against other P450 enzymes. The method was further improved by synthesis of testosterone specifically tritiated in the 6beta position, which displayed greatly improved conversion rate with an ensuing increase in assay sensitivity. Competition experiments using tritiated and unlabeled testosterone indicated that CYP3A4/5-mediated 6beta-hydroxylation exhibits positive cooperativity and a modest kinetic isotope effect. IC(50) values for more than 40 structurally diverse chemical inhibitors were not significantly different from those determined in the testosterone 6beta-hydroxylation assay, using HPLC-tandem mass spectrometry analysis. All the steps of the new assay, namely, incubation, product separation, and radioactivity counting, are performed in 96-well format and can be automated. This assay thus represents a high-throughput version of the classical testosterone 6beta-hydroxylation assay, which is the most widely used method to assess the potential for CYP3A4/5 inhibition of new chemical entities.
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PMID:Development and validation of a high-throughput radiometric CYP3A4/5 inhibition assay using tritiated testosterone. 1560 30

Human cytochrome P450 (CYP) 3A4 catalyzes the oxygen-dependent metabolism of greater than 60% of known drugs. CYP3A4 binds multiple ligands simultaneously, and this contributes to complex allosteric kinetic behavior. Substrates that bind to this enzyme change the ferric spin state equilibrium of the heme, which can be observed by optical absorbance and electron paramagnetic resonance (EPR) spectroscopy. The ligand-dependent spin state equilibrium has not been quantitatively understood for any ligands that exhibit multiple binding. The CYP3A4 substrate testosterone (TST) has been shown previously by absorbance spectroscopy to induce spin state changes that are characteristic of a low spin to high spin conversion. Here, EPR was used to examine the equilibrium binding of TST to CYP3A4 at [CYP3A4] > K(D), which allows for characterization of the singly occupied state (i.e., CYP3A4.TST). We also have used absorbance spectroscopy to examine equilibrium binding, where [CYP3A4] < K(D), which allows for determination of K(D)'s. The combination of absorbance and EPR spectroscopy at different CYP3A4 concentrations relative to K(D) and curve fitting of the resultant equilibrium binding titration curves to the Adair-Pauling equations, and modifications of it, reveals that the first equivalent of TST binds with higher affinity than the second equivalent of TST and its binding is positively cooperative with respect to ligand-dependent spin state conversion. Careful analysis of the EPR and absorbance spectral results suggests that the binding of the second TST induces a shift to the high spin state and thus that the second TST binding causes displacement of the bound water. A model involving six thermodynamic states is presented and this model is related to the turnover of the enzyme.
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PMID:The thermodynamic landscape of testosterone binding to cytochrome P450 3A4: ligand binding and spin state equilibria. 1566 29

The EtOAc-soluble fraction of the water extract of Piper cubeba, having shown potent inhibitory activity on the metabolism mediated by CYP3A4, was subjected to activity-guided isolation to yield two new lignans, (8R,8'R)-4-hydroxycubebinone (1) and (8R,8'R,9'S)-5-methoxyclusin (2), and two new sesquiterpenes, (5 alpha,8 alpha)-2-oxo-1(10),3,7(11)-guaiatrien-12,8-olide (3) and (1 alpha,2 beta,5 alpha,8 alpha 10 alpha)-1,10-epoxy-2-hydroxy-3,7(11)-guaiadien-12,8-olide (4), along with 16 known compounds (5-20). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. The compounds (8R,8'R,9'S)-5-methoxyclusin (2), (-)-clusin (10), (-)-yatein (13), ethoxyclusin (15), and (-)-dihydroclusin (17), having one methylenedioxyphenyl moiety in their structures, showed very potent and selective inhibitory activity against CYP3A4 with IC(50) values (0.44-1.0 microM) identical to that of the positive control, ketoconazole (IC(50), 0.72 microM).
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PMID:Potent CYP3A4 inhibitory constituents of Piper cubeba. 1567 19

The MeOH-soluble fraction of the water extract of Catharanthus roseus from Indonesia, having shown potent inhibitory activity on the metabolism mediated by CYP2D6, was subjected to activity-guided isolation to yield two triterpenes, ursolic acid (1) and oleanolic acid (2), and three alkaloids, vindoline (3), ajmalicine (4), and serpentine (5). The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-14C]erythromycin or [O-methyl-14C]dextromethorphan as a substrate, respectively. Ajmalicine (4) and serpentine (5) showed very potent inhibitory activity against CYP2D6 with IC50 values of 0.0023 and 3.51 microM, respectively. All isolated compounds showed weak or no inhibition against CYP3A4. On time-, concentration-, and NADPH-dependent assay, serpentine (5) appear to be the mechanism-based inhibitor for CYP2D6 enzyme in which the inhibition was irreversible and driven by catalytic process. K(I) and k(inact) values for serpentine (5) were 0.148 microM and 0.090 min-1, respectively. On the other hand, ajmalicine (4) showed no time-dependent inhibition or reversible inhibition, and thus appear to be not mechanism-based inhibitor.
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PMID:Cytochrome P450 2D6 (CYP2D6) inhibitory constituents of Catharanthus roseus. 1593 Jul 38

Four beta-glycosides of flavonoligan silybin, i.e. silybin beta-galactoside, silybin beta-glucoside, silybin beta-maltoside, silybin beta-lactoside were synthesized in order to improve silybin water solubility and bioavailability (Kren et al., J Chem Soc, Perkin Trans 1, 2467-2474, 1997). The presented paper deals with the effect of silybin and its synthetic beta-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 beta-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 beta-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.
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PMID:Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytes. 1597 88

The present interest and widespread use of herbal remedies has created the possibility of interaction between them and pharmaceutical drugs if they are used simultaneously. Before the recent reports of apparent hepatotoxicity associated with its use, kava (Piper methysticum Forst. F.), was one of the top 10 selling herbal remedies in Europe and North America. This adverse effect was not previously encountered with the traditional beverage which was prepared as a water infusion in contrast to the commercial products which are extracted with organic solvents. Kavalactones, the active principles in kava, are potent inhibitors of several of the CYP 450 enzymes, suggesting a high potential for causing pharmacokinetic interactions with drugs and other herbs which are metabolized by the same CYP 450 enzymes. Furthermore, some kavalactones have been shown to possess pharmacological effects, such as blockade of GABA receptors and sodium and calcium ion channels, which may lead to pharmacodynamic interactions with other substances which possess similar pharmacological proprieties. St. John's wort (Hypericum perforatum L.), used extensively for the treatment of mild to moderate clinical depression, has long been considered safer than the conventional pharmaceutical agents. However, its ability, through its active constituents hypericin, pseudohypericin and hyperforin, to induce intestinal P-glycoprotein/MRD1 and both intestinal and hepatic CYP3A4 enzyme, could markedly reduce the distribution and disposition of their co-substrates. In addition, St. John's wort is a potent uptake inhibitor of the neurotransmitters serotonin, norepinephrine and dopamine all of which have a role in mood control. Consequently, the very real potential for a pharmacodynamic interaction between the herb and pharmaceutical drugs which share this mechanism of action and, like St. John's wort, are used for mood elevation. However, presently there is very little evidence to substantiate actual pharmacokinetic and/or pharmacodynamic interaction between drugs and kava or St. John's wort. This review provides a brief overview of the existing data on interactions of kava and St. John's wort with pharmaceutical agents and as a result reveals the urgent need for detailed investigations to identify clinically significant interactions for these herbal remedies that have the potential to cause adverse effects.
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PMID:Potential for interaction of kava and St. John's wort with drugs. 1600 88

Cytochrome P450 (CYP) 3A4 is responsible for the oxidative degradation of more than 50% of clinically used drugs. By means of molecular dynamics simulations with the newly developed force field parameters for the heme-thiolate group and its dioxygen adduct, we examine the differences in structural and dynamic properties between CYP3A4 in the resting form and its complexes with the substrate progesterone and the inhibitor metyrapone. The results indicate that the broad substrate specificity of CYP3A4 stems from the malleability of a loop (residues 211-218) that resides in the vicinity of the channel connecting the active site and bulk solvent. However, the high-amplitude motion of the flexible loop is found to be damped out upon binding of the inhibitor or the substrate in the active site. In the resting form of CYP3A4, a structural water molecule is bound to the sixth coordination position of the heme iron, stabilizing the octahedral coordination geometry. In addition to the direct coordination of metyrapone to the heme iron, the hydrogen bond interaction between the inhibitor carbonyl group and the side chain of Ser119 also contributes significantly to stabilizing the CYP3A4-metyrapone complex. On the other hand, progesterone is stabilized in the active site by the formation of two hydrogen bonds with Ser119 and Arg106, as well as by the van der Waals interactions with the heme and hydrophobic residues. The structural and dynamic features of the CYP3A4-progesterone complex indicate that the oxidative degradation of progesterone occurs through hydroxylation at the C16 position by the reactive oxygen coordinated to the heme iron.
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PMID:Structural and dynamical basis of broad substrate specificity, catalytic mechanism, and inhibition of cytochrome P450 3A4. 1619 Jul 29

Cytochrome P450 (CYP) is a group of enzymes that metabolize drugs to a more water-soluble form, rendering them available for renal excretion. The major site of CYP expression is the liver. Nearly 50% of all medications currently on the market are metabolized by the enzyme CYP3A4, while metabolism of another 35-40% occurs through enzymes CYP1A2, CYP2C19, CYP2D6, CYP3A5 CYP3A6, and CYP3A7. Here, we summarize the current knowledge of the effects of hormones on the CYP family. The term "hormone" is used in its broad sense and includes products of the major endocrine glands (i.e., thyroid, adrenals, gonads, pancreas) and compounds that are not classically considered hormones, such as neurogenic amines, cytokines, interleukins, and eicosanoids. In addition, we comment on the effects on CYP expression of states associated with profound hormonal changes, such as pregnancy, malnutrition, obesity, diabetes mellitus, systemic inflammation, and conditions of altered extracellular fluid volume or osmolality. Available data are limited and are derived primarily from in vitro and animal studies. Moreover, the picture is obscured by conflicting results among studies and the complexity of the regulation of the expression and activity of elements of the CYP system. While the clinical significance of hormonal effects on the CYP system remains to be determined, we anticipate that such effects will be most pertinent to drugs with a narrow therapeutic range. Further research is needed to determine the scope and significance of these effects in view of rapid advances in the field of pharmacogenomics and the ever-increasing number of drugs available for therapeutic use.
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PMID:Hormonal effects on drug metabolism through the CYP system: perspectives on their potential significance in the era of pharmacogenomics. 1637 96


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