Pharmacogenomics of cytochrome P450 and other enzymes involved in biotransformation of xenobiotics

Guengerich, F. Peter

doi:10.1002/(sici)1098-2299(200001)49:1<4::aid-ddr2>3.0.co;2-r

Cited by 32 publications

(15 citation statements)

References 99 publications

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“…drugs) by P450s is a significant focus of scientists in the areas of toxicology, drug metabolism, and pharmacology. The effects of these oxidations can be manifested in poor drug bioavailability and various acute and chronic toxicities, including adverse drug interactions, cancer susceptibility, and birth defects [5]. Understanding the mechanism of drug metabolism by P450, in particularly the chemical reaction process, is indispensable in the early phases of drug discovery process.…”

Section: Introductionmentioning

confidence: 99%

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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Section: Introductionmentioning

confidence: 99%

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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“…Cytochrome P450 (CYP) enzymes are the major "Phase I" enzymes in liver microsomes that metabolize lipophilic drugs and pollutant molecules [1][2][3]. Most CYP enzyme reactions involve oxidation, although other reactions are known [4].…”

Section: Introductionmentioning

confidence: 99%

Thin film voltammetry of metabolic enzymes in rat liver microsomes

Krishnan

Rusling

2007

Electrochemistry Communications

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We report herein thin film voltammetry and kinetics of electron transfer for redox proteins in rat liver microsomes for the first time. Films were made layer-by-layer from liver microsomes and polycations on pyrolytic graphite electrodes. Cyclic voltammograms were chemically reversible with a midpoint potential of −0.48 V vs SCE at 0.1 V s −1 in pH 7.0 phosphate buffer. Reduction peak potentials shifted negative at higher scan rates, and oxidation-reduction peak current ratios were ∼1 consistent with non-ideal quasireversible thin film voltammetry. Analysis of oxidation-reduction peak separations gave an average apparent surface electron transfer rate constant of 30 s −1 . Absence of significant electrocatalytic reduction of O 2 or H 2 O 2 and lack of shift in midpoint potential when CO is added that indicates lack of an iron heme cofactor suggest that peaks can be attributed to oxidoreductases present in the microsomes rather than cytochrome P450 enzymes.

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“…They play a critical role in oxidation of xenobiotics including drugs and environmental pollutants and therefore represent a primary focus of toxicology and drug metabolism studies [5,7,16]. This group of enzymes (EC 1.14.14.1), estimated to contain about 4,000 members (http://drnelson.utmem.edu/P450.stats.all.htm), is classified into 17 families based on amino acid sequence similarity.…”

Section: Introductionmentioning

confidence: 99%

Preparative synthesis of drug metabolites using human cytochrome P450s 3A4, 2C9 and 1A2 with NADPH-P450 reductase expressed in Escherichia coli

Vail¹,

Homann²,

Hanna

et al. 2005

J IND MICROBIOL BIOTECHNOL

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Three human cytochrome P450s, 3A4, 2C9 and 1A2, were each co-expressed with NADPH-P450 reductase in Escherichia coli and used in the preparative synthesis of drug metabolites. Low dissolved oxygen (DO) concentration (<1%) during expression was found to be critical for producing active P450s. Control of temperature, pH and glycerol supplementation in 10-L fermentations enhanced enzyme expression 31-86%. Additional improvements were obtained by altering media formulations, resulting in bicistronic expression levels of 890, 1,800 and 1,010 nmol/L for 3A4, 2C9 and 1A2, respectively. The P450 titers achieved in fermentors exceeded those in flask fermentations by 3- to 6-fold in this study and up to 10-fold when compared with previously reported literature. Intact cells and isolated membranes obtained from 10-L fermentations were used to establish an efficient bioconversion system for the generation of metabolites. To demonstrate the utility of this approach, known metabolites of the anabolic steroid testosterone, the anti-inflammatory agent diclofenac and the analgesic agent phenacetin, were generated using 3A4, 2C9 and 1A2, respectively. The reaction conditions were optimized for pH, temperature, DO concentration, use of co-solvent and glucose supplementation. Conversion yields of 29-93% were obtained from 1-L reactions, enabling isolation of 59 mg 6beta-hydroxytestosterone, 110 mg 4'-hydroxydiclofenac and 88 mg acetaminophen.

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Pharmacogenomics of cytochrome P450 and other enzymes involved in biotransformation of xenobiotics

Cited by 32 publications

References 99 publications

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Thin film voltammetry of metabolic enzymes in rat liver microsomes

Preparative synthesis of drug metabolites using human cytochrome P450s 3A4, 2C9 and 1A2 with NADPH-P450 reductase expressed in Escherichia coli

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