Plasmid-mediated expression of the UmuDC mutagenesis proteins in an Escherichia coli strain engineered for human cytochrome P450 1A2-catalyzed activation of aromatic amines

Josephy, P. David; Evans, David H.; Williamson, V.; Henry, Tracey L.; Guengerich, F. Peter

doi:10.1016/s0027-5107(99)00120-7

Cited by 7 publications

(2 citation statements)

References 48 publications

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“…However, in terms of the 3D structures and the function of enzymes, P450 1A1 shows much more similarity to P450 1B1 than P450 1A2. In fact, P450 1A2 is largely responsible for the metabolism of aromatic amines, whereas P450s 1A1 and 1B1 metabolize polycyclic aromatic hydrocarbons and polyhalogenated aromatic hydrocarbons [2,107,108,109]. Furthermore, observations of crystal structures also show that similarity of active site cavities of P450s 1A1 and 1B1 is considerably more than that of P450s 1A1 and 1A2, indicating that selectively inhibiting P450s 1A1 and 1B1 is much more difficult than P450s 1A1 and 1A2 [1].…”

Section: Structural Characteristics Of P450s 1a1 and 1a2 Inhibitorsmentioning

confidence: 99%

Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships

2013

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With the widespread use of O-alkoxyresorufin dealkylation assays since the 1990’s, thousands of inhibitors of cytochrome P450 family 1 enzymes (P450s 1A1, 1A2, and 1B1) have been identified and studied. Generally, planar polycyclic molecules such as polycyclic aromatic hydrocarbons, stilbenoids, and flavonoids are considered to potentially be effective inhibitors of these enzymes. However, the details of structure-activity relationships and selectivity of these inhibitors are still ambiguous. In this review, we thoroughly discuss the selectivity of many representative P450 family 1 inhibitors reported in the past 20 years through a meta-analysis.

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Section: Structural Characteristics Of P450s 1a1 and 1a2 Inhibitorsmentioning

confidence: 99%

Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships

2013

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“…Cytochrome P450s 1A1, 1A2, and 1B1 are major P450 family I enzymes implicated in the detoxification and metabolic activation of drugs, environmental chemicals, and other xenobiotics. P450 1A2 largely metabolizes aromatic amines, whereas P450s 1A1 and 1B1 deal with the polycyclic aromatic hydrocarbons (PAHs) and polyhalogenated aromatic hydrocarbons (PHAHs). − PAHs are widely distributed environmental pollutants that ubiquitously occur as the byproducts of the petroleum industry, diesel-engine exhaust, cigarette smoke, and charcoal-grilled food . As toxicants, they are of concern because some of these compounds have been identified as carcinogenic, mutagenic, and teratogenic agents.…”

Section: Introductionmentioning

confidence: 99%

Ethynylflavones, Highly Potent, and Selective Inhibitors of Cytochrome P450 1A1

Goyal

Liu

Lovings

et al. 2014

Chem. Res. Toxicol.

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The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3′-Ethynylflavone, 4′-ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (KI values of 0.035–0.056 μM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (KI value of 0.51 μM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4′-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a Ki value of 0.035 μM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.

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The Escherichia coli lacZ reversion mutagenicity assay

Josephy

2000

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Plasmid-mediated expression of the UmuDC mutagenesis proteins in an Escherichia coli strain engineered for human cytochrome P450 1A2-catalyzed activation of aromatic amines

Cited by 7 publications

References 48 publications

Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships

Cytochrome P450 Family 1 Inhibitors and Structure-Activity Relationships

Ethynylflavones, Highly Potent, and Selective Inhibitors of Cytochrome P450 1A1

The Escherichia coli lacZ reversion mutagenicity assay

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