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PubMed1998

Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites.

Some cytochrome P450 catalyzed reactions show atypical kinetics, and these kinetic processes can be grouped into five categories: activation, autoactivation, partial inhibition, substrate inhibition, and biphasic saturation curves. A two-site model in which the enzyme can bind two substrate molecules simultaneously is presented which can be used to describe all of these observed kinetic properties. Sigmoidal kinetic characteristics were observed for carbamazepine metabolism by CYP3A4 and naphthalene metabolism by CYPs 2B6, 2C8, 2C9, and 3A5 as well as dapsone metabolism by CYP2C9. Naphthalene metabolism by CYP3A4 and naproxen metabolism by CYP2C9 demonstrated nonhyperbolic enzyme kinetics suggestive of a low Km, low Vmax component for the first substrate molecule and a high Km, high Vmax component for the second substrate molecule. 7, 8-Benzoflavone activation of phenanthrene metabolism by CYP3A4 and dapsone activation of flurbiprofen and naproxen metabolism by CYP2C9 were also observed. Furthermore, partial inhibition of 7, 8-benzoflavone metabolism by phenanthrene was observed. These results demonstrate that various P450 isoforms may exhibit atypical enzyme kinetics depending on the substrate(s) employed and that these results may be explained by a model which includes simultaneous binding of two substrate molecules in the active site.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

Cytochrome P4502E1 inhibition by propylene glycol prevents acetaminophen (paracetamol) hepatotoxicity in mice without cytochrome P4501A2 inhibition.

Acetaminophen hepatotoxicity is associated with its biotransformation to the reactive metabolite N-acetyl-p-benzoquinone imine that binds to protein. Two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated as primarily responsible for the bioactivation. To determine the relative contributions of these P450's, overnight fasted male NMRI mice were pretreated with 10 ml of 50% v/w propylene glycol/kg or fluvoxamine (10 mg/kg) at -80 and -20 min. relative to acetaminophen dosing to inhibit CYP2E1 and CYP1A2, respectively. Mice were sacrificed at 0.5 or 4 hr after a hepatotoxic dose of acetaminophen (300 mg/kg). Propylene glycol or propylene glycol plus fluvoxamine, but not fluvoxamine alone protected against acetaminophen hepatotoxicity as indicated by abolished increase in serum alanine aminotransferase activity, less depletion of hepatic glutathione and lower liver:body weight ratios. Propylene glycol inhibited the activity of CYP2E1 as indicated by 84% reduction in the clearance of 3 mg/kg dose of chlorzoxazone, whereas fluvoxamine inhibited the activity of CYP1A2 as indicated by 40% reduction in the clearance of a 10 mg/kg dose of caffeine. For this animal model, the data are consistent with the notion that hepatoxicity is associated with bioactivation of acetaminophen by CYP2E1 but not by CYP1A2.

Acetaminophen↗
PubMed2001

Nefiracetam metabolism by human liver microsomes: role of cytochrome P450 3A4 and cytochrome P450 1A2 in 5-hydroxynefiracetam formation.

An in-vitro study was conducted to investigate the metabolism of nefiracetam in human liver microsomes and to identify the enzymes responsible for the metabolism. Nefiracetam was hydroxylated by human liver microsomes to 5-hydroxynefiracetam (5-OHN). Eadie-Hofstee plots for the formation of 5-OHN suggested substrate activation. The kinetic parameters, apparent Km, Vmax, and Hill coefficient, for the formation of 5-OHN by pooled human liver microsomes were 4012 microM, 2.66 nmol min(-1) (mg protein)(-1), and 1.65, respectively. The formation of 5-OHN was significantly correlated with cytochrome P450 (CYP)3A4-mediated testosterone 6beta-hydroxylase activity and dextromethorphan N-demethylase activity. The 5-OHN formation was inhibited (94%) by antibody to human CYP3A4/5. The 5-OHN formation was also inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin, but not significantly inhibited by several other P450 inhibitors. The microsomes containing cDNA-expressed CYP3A4 formed 5-OHN with sigmoidal kinetics. CYP3A5-containing microsomes did not form 5-OHN. These results indicated that CYP3A, most likely CYP3A4, was the major isozyme responsible for the formation of 5-OHN in human liver microsomes. CYP1A2 and CYP2C19 microsomes were also capable of forming 5-OHN. However, the contribution of CYP1A2 was considered to be relatively minor compared with that of CYP3A4, and the contribution of CYP2C19 was assumed to be negligible, based on the result of the immunoinhibition study and taking into account both the turnover rate by each isozyme and the relative abundance of each isozyme in human liver. We conclude that on average the formation of 5-OHN, the major metabolite of nefiracetam, is principally mediated by CYP3A4 with a relatively minor contribution by CYP1A2.

Antibodies↗
PubMed1995

Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6.

The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine display the following rank order of in vitro potency against the cytochrome P450 (CYP) isoenzyme CYP2D6 as measured by their inhibition sparteine and/or dextromethorphan metabolism: paroxetine > fluoxetine identical to norfluoxetine > or = sertraline > or = fluvoxamine > venlafaxine. On this basis, paroxetine would appear to have the greatest and fluvoxamine and venlafaxine the least potential for drug interactions with CYP2D6-dependent drugs. In vivo, inhibitory potency is affected by the plasma concentration of the free (unbound) drug, a potentially important consideration since many CYP2D6-metabolised drugs exhibit nonlinear (saturable) kinetics, and by the presence of metabolites, which might accumulate and interact with the CYP system. Under steady-state conditions, paroxetine and fluoxetine are approximately clinically equipotent inhibitors of CYP2D6 in vivo (as determined through their effects on desipramine metabolism); sertraline, in contrast, shows lower steady-state plasma concentrations than fluoxetine and, hence, a less pronounced inhibition of CYP2D6. Of the drugs that are metabolised by CYP2D6, secondary amine tricyclic antidepressants, antipsychotics (e.g. phenothiazines, and risperidone), codeine, some antiarrhythmics (e.g. flecainide) and beta-blockers form the focus of clinical attention with regard to their potential interactions with the SSRIs. Coadministration of desipramine and fluoxetine (20 mg/day) at steady-state produced an approximately 4-fold elevation in peak plasma desipramine concentrations, while the long half-life of the active metabolite norfluoxetine was responsible for a significant and long lasting (approximately 3 weeks) elevation of plasma desipramine concentrations after discontinuation of fluoxetine. Similarly, coadministration of desipramine with paroxetine produced an approximately 3-fold increase in plasma desipramine concentration. In contrast, coadministration of desipramine and sertraline (50 mg/day) for 4 weeks resulted in a considerably more modest (approximately 30%) elevation in plasma desipramine concentrations. Coadministration of fluoxetine (60 mg/day, as a loading dose) [equivalent to serum concentrations obtained with 20 mg/day at steady-state] with imipramine or desipramine resulted in approximately 3- to 4-fold increases in plasma area under the curve (AUC) values for both imipramine and desipramine (illustrating a significant drug interaction potential at multiple isoenzymes). Consistent with its minimal in vitro effect on CYP2D6, fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine (approximately 3- to 4-fold increase in AUC) through inhibition of CYP3A3/4, CYP1A2, and CYP2C19. Thus, the extent of the in vivo interaction between the SSRIs and tricyclic antidepressants mirrors to a large extent their in vitro inhibitory potencies against CYP2D6 and other isoenzyme systems, especially if one takes into account pharmacokinetic factors.

Animals↗
PubMed1995

Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2.

Cytochrome P450 1A2 (CYP1A2) accounts for about 10 to 15% of the total CYP content of human liver and is the major enzyme involved in the metabolism of imipramine, propranolol, clozapine, theophylline, and caffeine. It is also involved in the conversion of heterocyclic amines to their proximal carcinogenic and mutagenic forms, as well as in the metabolism of endogenous substances, including 17 beta-estradiol and uroporphyrinogen III. Fluvoxamine is a potent inhibitor of CYP1A2, and there is potential for interaction with drugs that are metabolised by this isoenzyme. This property of fluvoxamine may be usefully applied to identifying agents that are substrates of CYP1A2, and it has a possible therapeutic application in the prevention of CYP1A2-mediated toxic metabolite formation.

Animals↗
PubMed2000

Effect of the adrenal 11-beta-hydroxylase inhibitor metyrapone on human hepatic cytochrome P-450 expression: induction of cytochrome P-450 3A4.

The drug metyrapone in the presence of glucocorticoid has been shown to induce the expression of rat hepatic cytochrome P-450 (CYP) 1A1 mRNA in vivo and in vitro through disruption of endogenous CYP1A1 regulator homeostasis and without either compound's binding to the aryl hydrocarbon receptor. Addition of metyrapone to human liver cancer cell cultures, with or without dexamethasone, did not induce CYP1A1 mRNA, in contrast to the aryl hydrocarbon receptor ligand beta-naphthoflavone. Addition of metyrapone to primary cultures of human hepatocytes also failed to induce detectable levels of CYP1A1 mRNA or CYP1A protein in two separate preparations, whereas the treatment with 2,3,7,8-tetrachlorodibenzo-rho-dioxin or omeprazole induced detectable levels of CYP1A1 mRNA in one preparation and CYP1A protein in both preparations. Addition of metyrapone to human hepatocyte cultures resulted in the induction of CYP3A4 expression. The pregnane X receptor (PXR), which has recently been shown to mediate the transcriptional induction of CYP3A4 expression in response to rifampicin, was activated by metyrapone in CV-1 cells transiently cotransfected with an expression vector encoding the human PXR and a reporter construct containing the everted repeat sequence that confers CYP3A4 induction responsiveness to inducers within its promoter. Metyrapone activated the human PXR at concentrations that also resulted in the induction of CYP3A4 in human cultured hepatocytes. Metyrapone treatment is therefore unlikely to result in the induction of CYP1A1 but may induce the expression of CYP3A4 in humans.

Animals↗
PubMed2001

Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009.

A variety of polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, arylamines, heterocyclic amines, and nitroarenes, were incubated with cDNA-based recombinant (Escherichia coli or Trichoplusia ni) systems expressing different forms of human cytochrome P450 (P450 or CYP) and NADPH-P450 reductase using Salmonella typhimurium tester strain NM2009, and the resultant DNA damage caused by the reactive metabolites was detected by measuring expression of umu gene in the cells. Recombinant (bacterial) CYP1A1 was slightly more active than any of four CYP1B1 allelic variants, CYP1B1*1, CYP1B1*2, CYP1B1*3, and CYP1B1*6, in catalyzing activation of chrysene-1,2-diol, benz[a]anthracene-trans-1,2-, 3,4-, 5,6-, and 8,9-diol, fluoranthene-2,3-diol, dibenzo[a,l]pyrene, benzo[c]phenanthrene, and dibenz[a,h]anthracene and several arylamines and heterocyclic amines, whereas CYP1A1 and CYP1B1 enzymes had essentially similar catalytic specificities toward other procarcinogens, such as (+)-, (-)-, and (+/-)-benzo[a]pyrene-7,8-diol, 5-methylchrysene-1,2-diol, 7,12-dimethylbenz[a]anthracene-3,4-diol, dibenzo[a,l]pyrene-11,12-diol, benzo[b]fluoranthene-9,10-diol, benzo[c]chrysene, 5,6-dimethylchrysene-1,2-diol, benzo[c]phenanthrene-3,4-diol, 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene, 5-methylchrysene, and benz[a]anthracene. We also determined activation of these procarcinogens by recombinant (T. ni) human P450 enzymes in S. typhimurium NM2009. There were good correlations between activities of procarcinogen activation by CYP1A1 preparations expressed in E. coli and T. ni cells, although basal activities with three lots of CYP1B1 in T. ni cells were very high without substrates and NADPH in our assay system. Using 14 forms of human P450s (but not CYP1B1) (in T. ni cells), we found that CYP1A2, 2C9, 3A4, and 2C19 catalyzed activation of several of polycyclic aromatic hydrocarbons at much slower rates than those catalyzed by CYP1A1 and that other enzymes, including CYP2A6, 2B6, 2C8, 2C18, 2D6, 2E1, 3A5, 3A7, and 4A11, were almost inactive in the activation of polycyclic aromatic hydrocarbons examined here.

Alleles↗
PubMed1987

Immunoquantitation of cytochrome b5 and methylcholanthrene-induced cytochromes P-450.

The enzyme-linked immunosorbent assay (ELISA) has been investigated for its ability to quantitate hydrophobic proteins like cytochromes b5 and P-450 at the subnanogram level. Issues encountered that have broad significance not only for ELISA, but for other qualitative and quantitative immunoassays as well, include the effects of detergent, the discriminatory capacity of ELISA, and the method for determining an assay's selectivity.

Animals↗
PubMed1987

Monoclonal antibodies inhibitory to rat hepatic cytochromes P-450: P-450 form specificities and use as probes for cytochrome P-450-dependent steroid hydroxylations.

Cytochrome P-450 (P-450) form specificities were established for a total of nine monoclonal antibodies (MAbs) raised to four distinct rat hepatic P-450 enzymes (P-450s 2c, PB-2a, PB-4, and BNF-B), using a combination of enzyme-linked immunosorbent analysis, dot immunoblotting, Western blotting, Ouchterlony immunodiffusion, and immunoinhibition analyses. Four of the MAbs were fully (greater than or equal to 85%) inhibitory toward the corresponding immunoreactive P-450s when assayed in purified, reconstituted enzyme systems, while two of the MAbs were partially inhibitory, with a maximum of 50 or 80% inhibition achieved in the presence of saturating MAb. Inhibitory MAbs reactive with P-450s 2c, 3, and PB-4, respectively, were used to demonstrate that the formation of multiple hydroxytestosterone metabolites by each of the respective purified P-450 enzymes is reflective of their inherent catalytic specificities and not due to the presence of immunochemical distinguishable P-450 enzyme contaminants. P-450 form-specific contributions to rat hepatic microsomal steroid hormone hydroxylase activities were then assessed using the inhibitory MAbs as probes. MAb-reactive P-450 2c was shown to be the major (greater than or equal to 85%) catalyst of microsomal testosterone and androstenedione 16 alpha-hydroxylation in both untreated and beta-naphthoflavone-induced rats. However, this P-450 form catalyzed only approximately 30% of hepatic microsomal steroid 16 alpha-hydroxylase activity in phenobarbital-induced adult males, and less than or equal to 10% of steroid 16 alpha-hydroxylase activity in (phenobarbital-induced immature males or adult females, where the balance of 16 alpha-hydroxylase activity is catalyzed by MAb-reactive P-450 PB-4. Although MAb-reactive P-450 PB-4 catalyzed the majority (greater than or equal to 90%) of microsomal androstenedione 16 beta-hydroxylation in phenobarbital-induced rats, this P-450 enzyme did not contribute to the low level 16 beta-hydroxylase activity of uninduced liver samples. Finally, MAb-reactive P-450 3 catalyzed at least 85% of microsomal androstenedione 7 alpha-hydroxylation, independent of the age, sex, or induction status of the animals used as source of liver microsomes. These findings demonstrate the usefulness of MAbs as probes for the contributions of individual P-450 enzymes to the metabolism of steroid hormones susceptible to hydroxylation at multiple sites.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1994

Catalytic selectivity and mechanism-based inactivation of stably expressed and hepatic cytochromes P450 2B4 and 2B5: implications of the cytochrome P450 2B5 polymorphism.

Cytochrome P450 (P450) 2B5 was recently found to be functionally distinct from three other rabbit P450 2B forms, based on androstenedione hydroxylase activities. In this investigation, we examined the frequency of the P450 2B5-null phenotype and the functional consequences of polymorphic P450 2B5 expression in hepatic microsomes from phenobarbital-treated rabbits. Four of the 10 animals examined did not have detectable levels of P450 2B5 mRNA and exhibited much lower microsomal androstenedione 15 alpha- and 16 alpha-hydroxylase activities. The 15 alpha-hydroxylase activity was found to correlate (r = 0.91) with liver P450 2B5 mRNA. P450 2B4 and 2B5 were stably expressed in human kidney 293 cells to further characterize substrate specificities and to investigate mechanism-based inactivation by phencyclidine. P450 2B4 was 4-16-fold more active than 2B5 towards benzphetamine, 7-ethoxycoumarin, methylenedioxybenzene, and pentoxyresorufin. Benzyloxyresorufin O-debenzylase activity was 160-fold higher for P450 2B4 than P450 2B5. Anti-P450 2B4 IgG inhibited benzyloxyresorufin O-debenzylation nearly completely in untreated and phenobarbital-induced liver microsomes. Phencyclidine selectively inactivated P450 2B4, compared with 2B5, in both human kidney 293 cell and liver microsomes. Poor inactivation of P450 2B5 by phencyclidine was found to be a result of its low maximal rate constant. Results of this study establish the idea that the metabolic consequences of phenobarbital induction depend on the potential of animals to express functionally variant P450 2B forms. Furthermore, we conclude that one or more of the 11 amino acid differences between these highly related P450 forms are critical to their substrate specificities and selective inactivation.

Androstenedione↗
PubMed1996

Inhibition and kinetics of cytochrome P4503A activity in microsomes from rat, human, and cdna-expressed human cytochrome P450.

Midazolam (MDZ) is metabolized in human liver microsomes by the cytochrome P450 (CYP) 3A subfamily to 1'-hydroxy (1'-OH) and 4-hydroxy (4-OH) metabolites. MDZ is metabolized in the rat primarily to 4-OH MDZ, 1'-OH MDZ, and 1',4-dihydroxy (1',4-diOH) MDZ. The kinetics of 4-OH and 1'-OH metabolite formation were determined using hepatic microsomes from control, Ro 23-7637 and dexamethasone-treated male rats. KM values for the major metabolite, 4-OH MDZ, were 24.5, 43.1, and 32.8 microM, and the corresponding Vmax values were 5.9, 28.9, and 13 nmol/mg/min for the control, DEX, and Ro 23-7637-treated animals, respectively KM values for 1'-hydroxylation of MDZ (the major metabolite) after incubation with human liver microsomes from three individuals were 5.57, 2.50, and 3.56 microM, and the corresponding Vmax values were 4.38, 0.49, and 0.19 nmol/mg/min, respectively. In parallel studies using cDNA-expressed human CYP3A4 microsomes, the KM for 1'-OH formation was 1.56 microM, and the corresponding Vmax was 0.16 nmol/mg/min. MDZ was not metabolized by cDNA-expressed human CYP2D6, CYP2E1, or CYP1A2, thus confirming that these isoforms were not responsible for its biotransformation. The formation of 1',4-diOH metabolite in rat and 1'-OH formation in cDNA-expressed human CYP3A4 microsomes showed a decrease in velocity at high substrate concentrations. Inhibition studies showed that MDZ hydroxylation was strongly inhibited by ketoconazole and Ro 23-7637 in rat, human, and cDNA-expressed human CYP3A4 microsomes. alpha-Naphthoflavone stimulated 1'-OH metabolite formation in human and cDNA-expressed human CYP3A4 microsomes at low concentration (10 microM). Naringenin, a flavonoid present in grapefruit juice, also inhibited MDZ metabolism in human liver microsomes. Immunoinhibition studies revealed that polyclonal anti-rat CYP3A2 antibody inhibited MDZ metabolism 80-90% in rat, human, and cDNA-expressed human CYP3A4 microsomes, thus suggesting that members of the CYP3A4 subfamily were involved in the metabolism.

Anesthetics, Intravenous↗
PubMed1998

Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir.

Both ritonavir and indinavir were readily metabolized by human intestinal microsomes. Comparison of the patterns of metabolites in incubations with enterocyte microsomes and expressed cytochrome P450 (CYP) isozymes and immunoinhibition and chemical inhibition studies showed the essential role of the CYP3A subfamily in the metabolism of both protease inhibitors by the small intestine. Ritonavir was similarly biotransformed by microsomes containing expressed CYP3A4 or CYP3A5 isozymes (KM = 0.05-0.07 microM, Vmax = 1-1.4 nmol/min/nmol CYP). In contrast, both the patterns of metabolites and the enzyme kinetic parameters for the metabolism of indinavir by expressed CYP3A5 (KM = 0.21 microM, Vmax = 0.24 nmol/min/nmol CYP) and CYP3A4 (KM = 0.04 microM, Vmax = 0.68 nmol/min/nmol CYP) were different. The biotransformation of both indinavir and ritonavir in human enterocyte microsomes was characterized by very low KM values (0.2-0.4 microM for indinavir and <0.1 microM for ritonavir). The Vmax for indinavir metabolism was greater in enterocyte (163 +/- 35 pmol/min/mg protein) than in liver (68 +/- 44 pmol/min/mg protein) microsomes. The metabolism of ritonavir in liver and enterocyte microsomes was associated with inactivation of CYP3A. The initial Vmax for ritonavir metabolism by enterocyte microsomes was 89 +/- 59 pmol/min/mg protein. The apparent inactivation rate constants for intestinal CYP3A and expressed CYP3A4 were 0.078 and 0.135 min-1, respectively. Metabolic inactivation of CYP3A by ritonavir explains the improved bioavailability and pharmacokinetics of ritonavir and the sustained elevation of blood levels of other, concomitantly administered, substrates of CYP3A.

Anti-HIV Agents↗
PubMed1983

Sequence homology of bacterial and mitochondrial cytochrome c oxidases. Partial sequence data of cytochrome c oxidase from Paracoccus denitrificans.

The aerobic electron transport chain of Paracoccus denitrificans is very similar to that of mitochondria. It has therefore been suggested that this bacterium might be evolutionarily related to mitochondria. The two subunits (Mr 45.000 and 28.000) of the Paracoccus cytochrome c oxidase were isolated and partially sequenced. The sequences were found to be surprisingly homologous to sequences of the subunits I and II of mitochondrial cytochrome c oxidases. The data provide a molecular basis for the symbiotic origin of mitochondria and strongly support the notion that in eucaryotic oxidases subunits I and/or II carry the redox centers, heme and copper.

Amino Acid Sequence↗
PubMed1986

Electrogenic proton exchange between cytochrome a3 active center and M-aqueous phase. Evidence for cytochrome a3-associated input proton well.

The rate of cyanide binding with the oxidized cytochrome-c oxidase in proteoliposomes is controlled by ionization of a protein group with pK approximately 6.7, the ligand reacting with the protonated enzyme only [(1983) Bioorg. Chem. (USSR) 9, 216-227]. As shown here, the kinetics of cyanide binding depends on the pH inside the proteoliposomes. The reaction rate is affected by the electrical potential difference across the proteoliposome membranes as if the a3-linked ionizable group exchanged H+ with the proteoliposome interior electrogenically. The data corroborate a hypothesis on the existence of a proton well communicating cytochrome oxidase O2-reducing center with the M-aqueous phase.

Animals↗
PubMed1987

Purification of all thirteen polypeptides of bovine heart cytochrome c oxidase from one aliquot of enzyme. Characterization of bovine fetal heart cytochrome c oxidase.

A protocol has been worked out for separating all thirteen different polypeptides in the beef heart cytochrome c oxidase complex from a single aliquot of enzyme. This involves an initial separation of polypeptides by gel filtration on a Biogel P-60 column in SDS, a step which purifies subunits CIV and CVIII and gives mixtures of CV + CVI, ASA, AED and STA, as well as CVII, CIX and IHQ. These mixtures are then resolved by reverse-phase high-performance liquid chromatography. The separation procedures have been applied to fetal heart cytochrome c oxidase of gestation between 100 and 200 days. No differences were found in the N-terminal sequences of any of the cytoplasmically made subunits or in the entire sequence of CIX between late fetal and adult forms of the enzyme.

Animals↗
PubMed1985

Inhibition of aromatase and NADPH cytochrome c reductase activities in human endometrium by the human placental NADPH cytochrome c reductase antiserum.

The cross-reactivity of human placental microsomal NADPH-cytochrome c reductase antiserum, REDFBIV, against the endometrial reductase alone and as a component of the endometrial aromatase was investigated. Human endometrial particulate fractions were incubated with various amounts of REDFBIV for 1 h at 4 degrees C and both enzyme activities were measured at the end of incubation. The extent of inhibition of these endometrial enzymes was compared with the ability of this antiserum to inhibit the placental microsomal reductase and aromatase activities. The antiserum effectively inhibited the activities of both enzymes in both tissues in a dose dependent manner with aromatase activity inhibited to a greater extent than reductase activity. These results indicate the antiserum to the placental microsomal NADPH-cytochrome c reductase component of aromatase recognizes the reductase component of the aromatase enzyme system in endometrium.

Aromatase Inhibitors↗
PubMed1991

Time-resolved magnetic circular dichroism spectroscopy of photolyzed carbonmonoxy cytochrome c oxidase (cytochrome aa3).

Nanosecond time-resolved magnetic circular dichroism (TRMCD) and time-resolved natural circular dichroism (TRCD) measurements of photolysis products of the CO complex of eukaryotic cytochrome c oxidase (CcO-CO) are presented. TRMCD spectra obtained at 100 ns and 10 microseconds after photolysis are diagnostic of pentacoordinate cytochrome a3Fe2+, as would be expected for simple photodissociation. Other time-resolved spectroscopies (UV-visible and resonance Raman), however, show evidence for unusual Fea3(2+) coordination after CO photolysis (Woodruff, W. H., O. Einarsdóttir, R. B. Dyer, K. A. Bagley, G. Palmer, S. J. Atherton, R. A. Goldbeck, T. D. Dawes, and D. S. Kliger. 1991. Proc. Nat. Acad. Sci. U.S.A. 88:2588-2592). Furthermore, time-resolved IR experiments have shown that photodissociated CO binds to CuB+ prior to recombining with Fea3(2+) (Dyer, R. B., O. Einarsdóttir, P. M. Killough, J. J. López-Garriga, and W. H. Woodruff. 1989. J. Am. Chem. Soc. 111:7657-7659). A model of the CcO-CO photolysis cycle which is consistent with all of the spectroscopic results is presented. A novel feature of this model is the coordination of a ligand endogenous to the protein to the Fe axial site vacated by the photolyzed CO and the simultaneous breaking of the Fe-imidazole(histidine) bond.

Binding Sites↗
PubMed1998

Non-inhibiting perturbation of the primary energy conversion site (Qo site) in Rhodobacter capsulatus ubihydroquinone: cytochrome c oxidoreductase (cytochrome bc1 complex).

Ethanol added to Rhodobacter capsulatus chromatophore membranes containing the cytochrome bc1 complex effectively uncouples the sensitivity of the [2Fe-2S] cluster EPR spectrum to the number and redox state of ubiquinone/ubihydroquinone within the Qo site. Ethanol has no effect upon the rate of catalysis, leading to a non-inhibiting perturbation of cytochrome bc1 function. We suggest that displacement occurs by ethanol acting from the aqueous phase to successfully compete with the Qo site ubiquinones and water to hydrogen bond the N(epsilon)H atom(s) of the coordinating [2Fe-2S] cluster histidines.

Binding Sites↗