Abstract：
:With the increased availability of human liver tissue, recombinant (cDNA-expressed) cytochrome P450 proteins (rCYPs), and knowledge of the human CYP pool (e.g. immunoquantitated levels of each CYP form in native liver microsomes), it is now possible to carry out in vitro "CYP reaction phenotyping" in an integrated manner. Reaction phenotyping allows one to identify which CYP form(s) is (are) involved in the metabolism of a given drug, using a combination of data obtained with native human liver microsomes and rCYP proteins. The following describes how one can attempt to integrate such data. A total of ten drugs are included in the analysis, represented by twelve reactions (six hydroxylations, two O-demethylations, one N-demethylation, one O-deethylation, and two sulfoxidations) that are largely catalyzed (> or =20%) by various combinations of CYPs (CYP3A4, CYP2C9, CYP1A2, and CYP2D6), and characterized by a wide range of apparent Km values (12-820 microM). Briefly, reaction rates measured with individual rCYPs are normalized with respect to the nominal specific content of the corresponding CYP in native human liver microsomes. In turn, the normalized rates for each rCYP are summed, yielding a "total normalized rate" (TNR), and the normalized rate for each rCYP is expressed as a percent of the TNR (% TNR). Finally, % TNR is related to inhibition (percent inhibition in the presence of CYP form selective chemical inhibitors; % I) and univariate regression analysis (r > or = 0.63; P < or = 0.05; N > or = 10 different livers) data obtained with native human liver microsomes. Therefore, the reaction phenotype of a drug is assigned by integrating all three data sets (r, % TNR, and % I).
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Rodrigues ADdoi
10.1016/s0006-2952(98)00268-8subject
Has Abstractpub_date
1999-03-01 00:00:00pages
465-80issue
5eissn
0006-2952issn
1873-2968pii
S0006295298002688journal_volume
57pub_type
杂志文章,评审abstract：:Addition of halothane to the incubation medium is shown to lower respiratory control and transmembrane potential and to increase ATPase activity in isolated rat liver mitochondria. Evidence is presented that L-carnitine is able to substantially decrease the negative effects of halothane on the energy-linked processes ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90011-0
更新日期：1986-11-15 00:00:00
abstract：:The effects of two competitive antagonists and two allosteric ligands on the rate of dissociation of [3H]N-methylscopolamine ([3H]NMS) were studied at atrial muscarinic acetylcholine M2 receptors by the technique of "infinite dilution." The dissociation rate for [3H]NMS, initiated by diluting the incubation mixture in...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(96)00814-3
更新日期：1997-03-21 00:00:00
abstract：:Clotrimazole is an antifungal azole derivative recently recognized as a calmodulin antagonist with promising anticancer effects. This property has been correlated with the ability of the drug to decrease the viability of tumor cells by inhibiting their glycolytic flux and consequently decreasing the intracellular conc...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.01.018
更新日期：2007-05-15 00:00:00
abstract：:To uncover the full spectrum of its pharmacological activities, the selective COX-2 inhibitor celecoxib is routinely being used at concentrations of up to 100 microM in cell culture. At these elevated concentrations, several COX-2-independent effects were identified, although many details of these events have remained...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.08.029
更新日期：2008-01-15 00:00:00
abstract：:Exogenous phosphatidic acid (PA) was observed to produce a concentration-dependent increase in [Ca(2+)](i) in cultured A10 vascular smooth muscle cells. Preincubation of cells with sarcoplasmic reticulum Ca(2+)-ATPase inhibitors (cyclopiazonic acid and thapsigargin), a phospholipase C inhibitor (2-nitro-4-carboxypheny...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(03)00201-6
更新日期：2003-06-15 00:00:00
abstract：:The spectrum of cytotoxicity of menadione (MD) was examined in a panel of human cancer cell lines. MD was equipotent against multidrug-resistant and parental leukemia cell lines with IC50 values of 13.5 +/- 3.6 and 18 +/- 2.4 microM respectively. A cervical carcinoma cell line resistant to the antimetabolite, methotre...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(91)90099-q
更新日期：1991-05-01 00:00:00
abstract：:Evidence has accumulated that deacetylation and acetylation events are implicated in the regulation of NF-kappaB transcriptional activity. Several groups have reported potentiation of NF-kappaB-mediated gene induction [by specific inducers (such as TNFalpha)], following deacetylase inhibition by trichostatin A or sodi...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2004.05.039
更新日期：2004-09-15 00:00:00
abstract：:We investigated the mechanism of phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells focusing on the p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (Hsp27) pathway. PMA-induced cell migration and activation of p38MAPK in A172 glioblastoma cells. PMA-induced formation of lam...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.06.018
更新日期：2007-09-01 00:00:00
abstract：:A hybrid molecule, which combines an anilinoacridine chromophore related to the antitumour drug amsacrine (m-AMSA) and a bispyrrole moiety analogous to the antiviral agent netropsin, has been examined for its ability to bind chromatin and to modulate the activity of topoisomerase II. The results show that the presence...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90564-y
更新日期：1992-02-04 00:00:00
abstract：:The effect of exhaustive exercise on the hepatobiliary transport of organic anions was investigated in rats. Animals were run on a rodent treadmill at 24 m/min up a 12% grade (152 +/- 15 min). Exercise resulted in significant hypoglycaemia (-46%) and increased plasma levels of lactate (+12%), together with a marked re...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90094-2
更新日期：1990-12-01 00:00:00
abstract：:Ribonucleotide reductase (RNR), which consists of R1 and R2 subunits, catalyzes a key step of deoxyribonucleoside triphosphate (dNTP) synthesis for DNA replication and repair. The R2 subunit is controlled in a cell cycle-specific manner for timely DNA synthesis and is negatively regulated by p53 in response to DNA dam...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2006.11.014
更新日期：2007-03-15 00:00:00
abstract：:Runt-related transcription factor 1 (RUNX1), one subunit of core-binding factors in hematopoiesis and leukemia, was highly expressed in ovarian cancer (OC), but the role of RUNX1 in OC is largely unknown. Since we found that high expression of RUNX1 is correlated with poor survival in patients with OC through bioinfor...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2020.114116
更新日期：2020-10-01 00:00:00
abstract：:The present study aimed to investigate endothelin-1 (ET-1) receptors in human and swine cardiomyocytes with binding studies using ET(A) and ET(B) selective receptor antagonists (BMS-182874 and BQ-788, respectively). Cell distribution of mRNA expression for ET(A) and ET(B) subtypes was investigated by in situ hybridiza...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(99)00081-7
更新日期：1999-07-15 00:00:00
abstract：:The non-sedating anti-histamine, loratadine [ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin- 11-ylidene-1-piperidinecarboxylate], was administered orally in the diet to mature male rats at dosages of 4, 10 and 25 mg/kg/day for 2 weeks. The effects of these treatments on liver microsomal cytochro...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90176-j
更新日期：1992-05-28 00:00:00
abstract：:Primary hepatocyte cultures derived from rat, rabbit, guinea pig and monkey have been treated in vitro with metabolites of di(2-ethylhexyl)phthalate, i.e. mono(2-ethylhexyl)phthalate (MEHP), mono(5-carboxy-2-ethylpentyl)phthalate (metabolite V) and mono(2-ethyl-5-oxohexyl)phthalate (metabolite VI). In rat hepatocyte c...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90223-j
更新日期：1993-06-22 00:00:00
abstract：:The activities of the xenobiotic metabolizing enzymes, aldehyde oxidase and xanthine oxidase, were determined in partially purified fractions of adult guinea-pig liver at given times in the day or night. A marked circadian variation in aldehyde oxidase activity was observed with several substrates (phthalazine, phenan...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(89)90185-8
更新日期：1989-05-01 00:00:00
abstract：:Rat liver microsomes and purified NADPH-cytochrome c reductase metabolized [14C]misonidazole anaerobically to a reactive intermediate that covalently binds to tissue macromolecules. Air strongly inhibited the binding whereas carbon monoxide had no effect, indicating that misonidazole is activated via reduction and not...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90158-7
更新日期：1982-02-15 00:00:00
abstract：:Antagonists of the chemokine receptor, CCR5, may provide important new drugs for the treatment of HIV-1. In this study we have examined the mechanism of action of two functional antagonists of the chemokine receptor CCR5 (UK-396,794, UK-438,235) in signalling and internalisation assays using CHO cells expressing CCR5....
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.06.032
更新日期：2007-09-15 00:00:00
abstract：:Isolated liver from phenobarbital-induced male mice was perfused using infusions of cytochrome c pulses as quality control of the system. Livers spontaneously evolved 1.1 pmoles ethane g-1 liver min-1, exogenous pentane disappeared with 0.6 pmoles g-1 min-1. Infusion of 0.26 mmoles/l. FeCl2 led to immediate ethane pro...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(83)90112-0
更新日期：1983-06-01 00:00:00
abstract：:The formation of morphine glucuronides is enantio- and regioselective in rats and humans. In rat liver microsomes, natural (-)-morphine formed only the 3-O-glucuronide, whereas the unnatural (+)-morphine formed glucuronides at both the 3-OH and 6-OH positions, with the 6-O-glucuronide being the principal product. In h...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(89)90625-4
更新日期：1989-10-01 00:00:00
abstract：:Previous studies of platinum(II) compounds with bidentate leaving ligands have emphasized the contrast between the stability of the bidentate leaving ligand in vitro (T1/2 greater than 11 days in water) and the apparent reactivity of these bidentate platinum compounds in vivo. However, none of these studies actually m...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(88)90646-6
更新日期：1988-09-01 00:00:00
abstract：:Following the administration of latex particles (0.46 micron), cytochrome P-450 dependent monooxygenase system was depressed in the livers of mice. These particles were taken up exclusively by Kupffer cells in the liver, and no particles were found in the hepatocytes which contain most of the monooxygenase capacity in...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90114-0
更新日期：1986-05-01 00:00:00
abstract：:Using the incorporation of [3H]isoleucine or [3H]hypoxanthine into acid-insoluble products as indices of protein- and nucleic acid-synthetic activity, respectively, it was shown that seven plant-derived quassinoids with differing chemical substitutions all inhibited protein synthesis more rapidly than nucleic acid syn...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(89)90644-8
更新日期：1989-12-15 00:00:00
abstract：:This paper presents data on the effects of benfluron and its two metabolites DBF and NOBF on both endogenous and exogenous, respiration in the presence of succinate as substrate, of both P388 murine leukemia and Ehrlich ascites carcinoma cells. The most efficient inhibitors of endogenous and exogenous respiration were...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(91)90413-y
更新日期：1991-12-11 00:00:00
abstract：:The alcohol-avoiding ANA (Alko, Non-Alcohol) and alcohol-preferring AA (Alko, Alcohol) rat lines are known to differ in their acetaldehyde metabolism and were originally found to differ in hepatic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities in the 1970s. At the beginning of the 1980s, thes...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90199-6
更新日期：1994-10-18 00:00:00
abstract：:The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioural effects were invest...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2013.04.017
更新日期：2013-06-15 00:00:00
abstract：:Homocysteine has been shown to increase glutathione levels in C3H/10T1/2 Cl 8 cells. The present paper confirms that this increase was specific for non-dividing cells. Several other thiols and disulfides, including cysteamine, mercaptoethanol and dithioerythritol, also increased glutathione, but the specificity for qu...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90046-n
更新日期：1990-02-01 00:00:00
abstract：:Studies were performed to investigate the irreversible binding and oxidative metabolism of propranolol in human liver microsomes and the relationship of binding and metabolism to the polymorphic oxidation of debrisoquine. Incubation of microsomes with 14C-labelled propranolol in the presence of a NADPH-generating syst...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90592-2
更新日期：1987-07-15 00:00:00
abstract：:Arsenic trioxide (ATO) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, but successful application of this agent may occasionally require the use of sensitizing strategies. The present work demonstrates that the flavonoids quercetin and chrysin cooperate with ATO to induce apoptosis...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2008.02.007
更新日期：2008-05-15 00:00:00
abstract：:Isolated rat liver mitochondria have been incubated in the presence of the general anesthetic 2,6-diisopropylphenol (0-100 microM) and the efficiency of oxidative phosphorylation has been evaluated by measuring the respiratory rates, the rates of ATP synthesis or hydrolysis and the magnitude of the transmembrane elect...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(91)90684-w
更新日期：1991-06-21 00:00:00
