Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.14.13.97 (CYP3A4)
6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CYP3A4 is the major human cytochrome P-450 in a superfamily of heme-thiolate proteins that catalyze the oxidation of numerous lipophilic compounds. In this investigation, we report that CYP3A4 requires a phenolic function for ortho hydroxylation of estradiol and mono-O-demethylated methoxychlor and that CYP3A4 aromatic hydroxylation in general may be dependent on the presence of a free phenolic group. Indeed, when methoxyls were present instead of phenolic hydroxyls, CYP3A4 essentially failed to catalyze ortho hydroxylation. By contrast, of eight additional cDNA-expressed P-450s (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, and 2E1) examined, only CYP1A2 and CYP2B6 could catalyze ortho hydroxylation of [o-3H]methoxychlor (7.2 and 14.6 pmol/90 min/pmol P-450, respectively), indicating that these isoforms do not require a phenolic hydroxyl for aromatic hydroxylation and that methoxyls do not sterically hinder catalysis by these CYPs. However, with [o-3H]mono-O-demethylated methoxychlor, containing a phenolic group, five isoforms (CYP1A2, 2B6, 2D6, 2E1, and 3A4) supported ortho hydroxylation. Of these, CYP3A4 exhibited by far the highest rate of hydroxylation at 87.8 pmol/90 min/pmol P-450. Further studies with [2-(3)H]estradiol 3-methyl ether and with [2-(3)H]estradiol revealed a similar and dramatic augmentation of CYP3A4-mediated C2 hydroxylase activity of approximately 75-fold by the presence of the phenolic group in the 3-position. The mechanism of augmentation by the phenolic hydroxyl does not appear to involve the acidic proton of estradiol, since CYP3A4-catalyzed estradiol 2-hydroxylation and testosterone 6-beta-hydroxylation were diminished to an equal extent when incubations were performed at increasing buffer pH values from 7 to 9. Both estradiol and its 3-methoxy derivative bound with similar affinity to cDNA-expressed, microsomal CYP3A4: spectral dissociation constants were 270 and 370 microM, respectively, and both compounds exhibited type I spectra. Thus, the disparities in aromatic hydroxylation rates between compounds containing phenolic hydroxyls and those with methoxyls cannot be explained by differences in their binding affinities. To explain the mode via which the phenolic hydroxyl facilitates ortho hydroxylation, a mechanism in which the phenolic moiety attacks the iron-oxo double bond of CYP3A4, resulting in oxygen transfer to the ortho position, is proposed. It is anticipated that these findings will assist in forecasting the CYP-mediated metabolic fate of phenolic compounds.
...
PMID:Catalytic characteristics of CYP3A4: requirement for a phenolic function in ortho hydroxylation of estradiol and mono-O-demethylated methoxychlor. 904 21

The pharmacokinetics of many drugs often vary considerably among individuals, largely because of variations in the expression of different cytochrome P-450 (CYP) enzymes in the liver and other tissues. Relatively selective substrate probes in vivo have been discovered for several major CYP isoforms involved in oxidative drug metabolism. Regarding isoforms that show genetic polymorphism (CYP2C19 and CYP2D6), genotyping as well as phenotyping with appropriate probe drugs can be used to distinguish between "poor" and "extensive" metabolizers. Measurement of CYP2D6 activity, which is being performed increasingly by means of genotyping, has an established role in the individualization of the dosage of selected CYP2D6 substrates. However, the therapeutic implications of extremely high CYP2D6 activity in some patients (ultrarapid metabolizers) need more attention. The therapeutic consequences of CYP2C19 polymorphism are not as well characterized as those of CYP2D6 polymorphism, but are likely to be of little significance with most CYP2C19 substrates. Probe-based assays are also available for measurement of in vivo activity of CYP1A2, CYP2E1 and CYP3A4; those will be discussed in detail in this review. These tests can be used, for example, to compare the activity of a specific isoform among patients and to characterize effects of such environmental factors as drugs and compounds in the diet on enzyme activity. However, it should be recognized that attempts to develop valid probe-based assays of in vivo activity of specific, nonpolymorphic CYP isoforms have proved relatively difficult; for example, none of the several putative probes of CYP3A4, the most important drug-metabolizing CYP isoform, is completely satisfactory. It is now clear that many diverse factors must be considered in the validation of these tests.
...
PMID:Use of probe drugs as predictors of drug metabolism in humans. 904 84

Using in vitro techniques, the present study demonstrates that CYP2D6, and 3A4 are involved in N-demethylation of citalopram (CIT) enantiomers. Human liver microsome incubations performed with specific inhibitors of these three CYP isozymes have shown up to 60% inhibition of demethylcitalopram production. cDNA expressed human cytochrome P-450 3A4, 2C19 and 2D6 isozymes, but not CYP1A2, were identified to be involved in N-demethylation of CIT enantiomers. Kinetics using cDNA expressed CYP2C19 and CYP3A4 show K(m) values in the same range: 198 microM, 211 microM for CYP2C19 and 169 microM, 163 microM for CYP3A4 for S- and R-CIT demethylation, respectively. In contrast, kinetics using cDNA expressed CYP 2D6 show a K(m) of 18 microM and 22 microM for S- and R-CIT demethylation, respectively. Nevertheless, kinetics using cDNA expressed CYP2C19 and 3A4 have a range of Vmax values ten times higher than that of CYP2D6. For this reason, intrinsic clearance values (Vmax/K(m)) for S- and R-CIT were within a small range for these three isozymes: 0.25 to 0.39 microliter h-1 x pmol-1 of CYP. CYP2D6 has an opposite stereoselectivity in the biotransformation of CIT enantiomers than CYP2C19 and 3A4; the S/R ratios of the intrinsic clearance were 0.71, 1.57 and 1.37, respectively. Taking into account that CYP isozymes are expressed at various levels, CYP2D6, which is expressed at lower levels than CYP2C19 and CYP3A4, plays a minor role in the biotransformation of CIT enantiomers. These results confirm that the use of cDNA expressed CYP isozymes is a potent tool for the measurement of kinetic constants and help to predict clearance modifications of CIT enantiomers, especially in poor metabolizers of mephenytoin (with a CYP2C19 deficiency) or patients comedicated with potent CYP2C19 or 3A4 inhibitor(s). For instance, fluvoxamine (100 microM) inhibits CIT N-demethylation by 64% in microsomes.
...
PMID:Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes. 911 Mar 56

Seven of the newest antidepressants are the serotonin-selective reuptake inhibitors (fluoxetine, sertraline, paroxetine, and fluvoxamine [currently approved in the United States only for obsessive-compulsive disorder]), a serotonin-norepinephrine reuptake inhibitor (venlafaxine), a postsynaptic serotonin antagonist-presynaptic serotonin reuptake inhibitor (nefazodone), and a presynaptic-postsynaptic noradrenergic-serotonergic receptor antagonist (mirtazapine). Many of these drugs are potent inhibitors of the cytochrome P-450 enzymes (CYPs) of the liver. The isoforms of the CYPs most relevant to the use of antidepressants are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP inhibition may affect the metabolism of numerous drugs in several classes that are substrates for these isoenzymes, with potentially serious consequences. To minimize the potential for an adverse event, the practitioner must remember the drug-drug interactions, and possible consequences when one of these antidepressants is being prescribed. A "primer" on drug metabolism is included herein, which serves as a basis for understanding these interactions., Each of the isoenzymes of the CYPs is discussed in relationship to the drugs they metabolize, and appropriate cautions are recommended for concurrent administration of these new antidepressants and other drugs most frequently prescribed to elderly patients.
...
PMID:Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs. 929 31

The effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems with respect to three cytochrome P-450 isozymes in rat liver microsomes were investigated. FK-506 non-competitively inhibited the aniline p-hydroxylase, p-nitroanisole O-demethylase and lidocaine N-deethylase activities of cytochrome P-450-linked monooxygenase systems, these activities being mainly catalyzed by cytochromes P-450 CYP2E1, CYP2C11 and CYP3A4, respectively, and the Ki values of the activities for FK-506 were determined to be 605, 491 and 97 microM, respectively. The inhibition of cytochrome P-450-linked monooxygenase systems by FK-506 seemed to involve the direct inhibition of cytochromes P-450 because the NADPH-cytochrome c reductase and NADPH-ferricyanide reductase activities of NADPH-cytochrome P-450 reductase were not affected by the presence of 1 mM FK-506 at all. A spectrophotometric study showed that a reverse type I spectral change was induced on the addition of FK-506 to rat liver microsomes, and the Ks value was apparently 125 microM. On the other hand, the EPR spectra of cytochromes P-450 in rat liver microsomes were not affected by 1 mM FK-506. These results suggest direct interaction between FK-506 and cytochrome P-450 apoproteins, except for the heme iron regions of cytochromes P-450, resulting in inhibition of the drug-metabolism activities catalyzed by cytochromes P-450.
...
PMID:Effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems in rat liver microsomes. 930 7

Recent technologies have resulted in an explosion of information concerning the cytochrome P-450 isoenzymes and increased awareness of life-threatening interactions with such commonly prescribed drugs as cisapride and some antihistamines. Knowledge of the substrates, inhibitors, and inducers of these enzymes assists in predicting clinically significant drug interactions. In addition to inhibition and induction, microsomal drug metabolism is affected by genetic polymorphisms, age, nutrition, hepatic disease, and endogenous chemicals. Of the more than 30 human isoenzymes identified to date, the major ones responsible for drug metabolism include CYP3A4, CYP2D6, CYP1A2, and the CYP2C subfamily.
...
PMID:Update: clinically significant cytochrome P-450 drug interactions. 969 71

The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of alprazolam was investigated. Fourteen subjects who completed the study received a single 1 mg dose of alprazolam without or with concomitant sertindole 12 mg daily. Coadministration of sertindole and alprazolam led to a half-hour decrease (P < 0.05) in mean Tmax value (alone: 1.2 h, in combination: 0.7 h) and a 1.6-h increase in the mean t1/2 value (12.5 +/- 3.2 versus 14.3 +/- 3.4 h, P < 0.05) of alprazolam. The mean Cmax (18.5 +/- 4.9 versus 18.5 +/- 4.8 ng/ml) and AUC (266 +/- 68 versus 275 +/- 57 ng x h/ml) values of alprazolam did not change statistically significantly in the presence of sertindole (P > 0.05). These pharmacokinetic changes are minor and not considered to be of clinical significance. Although both sertindole and alprazolam are substrate for CYP3A4 (cytochrome P-450 3A4), the results in this study suggest that sertindole is not an inhibitor of the metabolism of alprazolam.
...
PMID:Lack of multiple dosing effect of sertindole on the pharmacokinetics of alprazolam in healthy volunteers. 949 26

beta-Arteether (AE) is an endoperoxide sesquiterpene lactone derivative currently being developed for the treatment of severe, complicated malaria caused by multidrug-resistant Plasmodium falciparum. Studies were undertaken to determine which form(s) of human cytochrome P-450 catalyze the conversion of beta-arteether to its deethylated metabolite, dihydroqinghaosu (DQHS), itself a potent antimalarial compound. In human liver microsomes, AE was metabolized to DQHS with a Km of 53.7 +/- 29.5 microM and a Vmax of 1.64 +/- 1. 78 nmol DQHS/min/mg protein. AE biotransformation to DQHS was inhibited by ketoconazole and troleandomycin. Ketoconazole was a competitive inhibitor, with an apparent Ki of 0.33 +/- 0.11 microM. Because AE is being developed for patients who fail primary treatment, it is possible that AE may be involved in life-threatening drug-drug interactions, such as the associated cardiotoxicity of mefloquine and quinidine. Coincubation of AE with other antimalarials showed mefloquine and quinidine to be competitive inhibitors with a mean Ki of 41 and 111 microM, respectively. Metabolism of AE using human recombinant P450s provided evidence that cytochrome P450s 2B6, 3A4, and 3A5 were the primary isozymes responsible for its deethylation. CYP3A4 metabolized AE to dihydroqinghaosu at a rate approximately 10 times that of CYP2B6 and approximately 4.5-fold greater than that of CYP3A5. These results demonstrate that CYP3A4 is the primary isozyme involved in the metabolism of AE to its active metabolite, DQHS, with secondary contributions by CYP2B6 and -3A5.
...
PMID:Metabolism of beta-arteether to dihydroqinghaosu by human liver microsomes and recombinant cytochrome P450. 953 17

The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of terfenadine was investigated. Thirteen subjects who completed the study received a single 120 mg dose of terfenadine alone or with concomitant 20 mg sertindole daily. The mean values for terfenadine Cmax (alone: 2.42 +/- 1.48 ng/ml, in combination: 2.99 +/- 1.85 ng/ml) and AUC (29.6 +/- 18.9 vs 37.9 +/- 23.4 ng x hr/ml) did not change statistically significant in the presence of sertindole (p > 0.05). Similarly, the mean Cmax (531 +/- 195 vs 506 +/- 190 ng/ml) and AUC (3,728 +/- 1,163 vs 4,003 +/- 1,739 ng x hr/ml) values of carboxyterfenadine did not change statistically significant in the presence of sertindole (p > 0.05). The other pharmacokinetic parameters of terfenadine and carboxyterfenadine such as Tmax, t1/2, as well as the carboxyterfenadine to terfenadine Cmax and AUC ratios did not change in the presence of sertindole. Although terfenadine is a substrate for CYP3A (cytochrome P-450 3A), while sertindole is a substrate for both CYP2D6 and CYP3A4, the results in this study suggest that sertindole, at a clinical dose, is not an inhibitor of the metabolism of terfenadine.
...
PMID:Lack of CYP3A inhibition effects of sertindole on terfenadine in healthy volunteers. 956 30

Diethyldithiocarbamate methyl ester (DDTC-Me) is a precursorto the formation of S-methyl-N,N-diethylthiolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P-450 (CYP) enzymes in sulfoxidation and thiono-oxidation of DDTC-Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P-450 enzyme(s) involved in the sulfoxidation and thiono-oxidation of DDTC-Me. These approaches included the use of cDNA-expressed human P-450 enzymes, correlation analysis with sample-to-sample variation in human P-450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P-450 enzymes (CYP3A4, CYP1A2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC-Me, as determined with cDNA-expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC-Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC-Me sulfoxidation and testosterone 6beta-hydroxylation; (2) increased DDTC-Me sulfoxidation in the presence of alpha-naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC-Me sulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono-oxidation of DDTC-Me by human liver microsomes is catalyzed in part by CYP1A2, CYP2B6, CYP2E1, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA-expressed enzymes; (2) a high correlation between DDTC-Me thiono-oxidation and testosterone 6beta-hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti-CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC-Me thiono-oxidation by furafylline and anti-CYP1A antibody suggested involvement of CYP1A2; and (5) inhibition of DDTC-Me thiono-oxidation by DDTC and anti-CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC-Me by human liver microsomes, and CYP1A2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC-Me thiono-oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153-1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.
...
PMID:Identification of the human P-450 enzymes responsible for the sulfoxidation and thiono-oxidation of diethyldithiocarbamate methyl ester: role of P-450 enzymes in disulfiram bioactivation. 975 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---