Predicting the cytochrome P450 mediated metabolism of xenobiotics

Korzekwa, Kenneth R.; Jones, Jeffery P.

doi:10.1097/00008571-199302000-00001

Cited by 113 publications

(80 citation statements)

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“…In this same study, a series of partial or modified structures of 7,8-benzoflavone were tested for their ability to activate or inhibit the metabolism of phenanthrene, chrysene, and benzo-[a]pyrene in vitro (Shou et al, 1994) to determine the effector structural features necessary for the activation of CYP3A4. However, similar studies to determine the structural requirements for activation of CYP2C9 have yet to be performed, although many structureactivity studies have been conducted in an effort to better understand substrate and inhibitor binding to CYP2C9 (Korzekwa and Jones, 1993;Mancy et al, 1995;Jones et al, 1996a;Afzelius et al, 2001). To this end, we have explored the modulation of CYP2C9-mediated metabolism by nine analogs of dapsone and assessed their effects on the metabolism kinetics of flurbiprofen and naproxen, two prototypical substrates for CYP2C9.…”

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confidence: 99%

Activation of CYP2C9-Mediated Metabolism by a Series of Dapsone Analogs: Kinetics and Structural Requirements

Hutzler¹,

Kolwankar²,

Hummel³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 2C9-mediated metabolism has been shown to be activated in the presence of the effector dapsone. However, it has yet to be established what effector structural features are necessary to activate CYP2C9 activity. To address this question, kinetic studies were conducted with nine analogs of dapsone containing various functional properties (three sulfone compounds, three carbonyl compounds, and three sulfonamide compounds), to examine the functional groups important for enzyme activation by the effector (dapsone). Results show that phenylsulfone (dapsone without the paraamino groups) activates flurbiprofen 4-hydroxylation comparable to dapsone but inhibits naproxen demethylation. Meanwhile, p-tolylsulfone had little effect on flurbiprofen metabolism, but activated naproxen demethylation, albeit only at high concentrations. These substrate-dependent differences in effect suggest that naproxen has a different binding orientation compared with flurbiprofen. Perhaps most interesting is that replacement of only one amino group from dapsone with a nitro group (4-(4-nitrophenylsulfonyl)-aniline) resulted in substantial inhibition of flurbiprofen 4-hydroxylation, suggesting that electronic effects may influence activation of this substrate. Other analogs either had minor or no effect on CYP2C9-mediated metabolism. Overall, it is apparent from these studies that a sulfone group in direct association with two benzene rings with paraelectron-donating groups represents the most efficient activator of CYP2C9. However, the effects of these analogs appear to be concentration-and substrate-dependent, further complicating the prediction of these types of in vitro interactions.Cytochrome P450 (P450 1 ) enzymes are a superfamily of enzymes responsible for metabolizing a wide range of endogenous and xenobiotic compounds (Wrighton and Stevens, 1992;Guengerich, 1995). Within this superfamily, CYP2C9 is known to be an important isoform responsible for metabolizing many relevant compounds such as (S)-warfarin (Rettie et al., 1992), phenytoin and tolbutamide (Veronese et al., 1991), as well as many nonsteroidal anti-inflammatory drugs (Miners and Birkett, 1998). Consequently, factors that modulate the activity of this enzyme are of substantial interest to the drug industry, as well as to academic scientists, since the resultant effects may alter a drug's therapeutic efficacy or toxicity.Our lab has determined that CYP2C9 often does not follow normal Michaelis-Menten kinetics. For example, CYP2C9-mediated flurbiprofen 4Ј-hydroxylation has been shown to be activated by the effector dapsone in human liver microsomes and baculovirus-expressed CYP2C9 (Korzekwa et al., 1998). In addition, kinetic studies on the activation of flurbiprofen 4Ј-hydroxylation, as well as naproxen demethylation by dapsone have recently been reported (Hutzler et al., 2001). Data from this kinetic study were fit to a two-site effector model equation that resulted in an increase in the V max and a decrease in the K m parameter estimates for the me...

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confidence: 99%

Activation of CYP2C9-Mediated Metabolism by a Series of Dapsone Analogs: Kinetics and Structural Requirements

Hutzler¹,

Kolwankar²,

Hummel³

et al. 2002

Drug Metab Dispos

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“…The CYP enzymes catalyze the activation of molecular oxygen to a reactive monooxygen species (3), which can oxidize a variety of compounds (4). The transition state for the hydrogen-atom abstraction reaction is not, however, stabilized by the enzyme (3). Furthermore, the energetics of the active oxygen species is conserved among the several CYP enzymes studied (5 Preparation of Pyridine-Induced Rat Liver Microsomes.…”

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confidence: 99%

“…ln(rate, CYP2E1) = 46.99 -1.77(AHact) [3] Leave-one-out cross-validation was carried out to validate the predictive ability of the PNR model ( Table 1). The cross-validated predicted rates of reaction reflect the ability of the model to predict the rate of reaction of a given compound that is not included in the model.…”

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confidence: 99%

Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes.

Yin

Anders

Korzekwa

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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A computational model is presented that can be used as a tool in the design of safer chemicals. This model predicts the rate of hydrogen-atom abstraction by cytochrome P450 enzymes. Excellent correlations between biotransformation rates and the calculated activation energies (AHact) of the cytochrome P450-mediated hydrogen-atom abstractions were obtained for the in vitro biotransformation of six halogenated alkanes (1-fluoro-1,1,2,2-tetrachloroethane, 1,1-difluoro-1,2,2-trichloroethane, 1,1,1-trifluoro-2,2-dichloroethane, 1,1,1,2-tetrafluoro-2-chloroethane, 1,1,1,2,2-pentafluoroethane, and 2-bromo-2-chloro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: ln(rate, rat liver microsomes) = The design of chemicals with lowest possible toxicity would decrease the damage to the environment; decrease the costs of production, health care, and site remediation; and increase the safety in the workplace (1). Although many factors are involved in the design of safer chemicals, one significant aspect is the prediction of rates of bioactivation of protoxins and procarcinogens to toxic metabolites (2). Bioactivation plays a major role in the toxicity of many chemicals, and the most important enzymes involved are the cytochromes P450 (CYPs) (2). The CYP enzymes catalyze the activation of molecular oxygen to a reactive monooxygen species (3), which can oxidize a variety of compounds (4). The transition state for the hydrogen-atom abstraction reaction is not, however, stabilized by the enzyme (3). Furthermore, the energetics of the active oxygen species is conserved among the several CYP enzymes studied (5). These factors make the CYP enzymes ideal candidates for predictive computational methods.We describe herein the application of a computational method for predicting the CYP-mediated oxidation rates of halogenated alkanes. Developing strategies for the design of safer halogenated alkanes is a particularly relevant objective, since hydro (chloro) Chemicals. 1-Fluoro-1,1,2,2-tetrachloroethane (HCFC-121), 1,1-difluoro-1,2,2-trichloroethane (HCFC-122), 1,1,1-trifluoro-2,2-dichloroethane (HCFC-123), 1,1,1,2-tetrafluoro-2-chloroethane (HCFC-124), pentafluoroethane (HFC-125), dichlorofluoroacetic acid, and chlorodifluoroacetic acid were obtained from PCR Research Chemicals (Gainesville, FL) and were used as received. 2-Bromo-2-chloro-1,1,1-trifluoroeth-

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“…Interestingly, rat CYP2B1 has high catalytic rates for the metabolism of (ϩ)-and (Ϫ)-limonene enantiomers, whereas the orthologous human enzyme, CYP2B6, does not oxidize limonene metabolism capacity at all Shimada et al, 2002b). These results collectively indicated that natural terpene compounds in the environment are differentially oxidized by different P450 enzymes in several animal species and that the structures of these chemicals determine which molecules are attacked by P450 enzymes (Korzekwa and Jones, 1993;Lewis, 1998;Dai et al, 2000). Further work will be required to determine how these terpene compounds cause biological and toxicological responses in animal species, including humans.…”

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confidence: 96%

Roles of Human Cyp2a6 and 2b6 and Rat Cyp2c11 and 2b1 in the 10-Hydroxylation of (–)-Verbenone by Liver Microsomes

Miyazawa¹,

Sugie²,

Shimada³

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:(؊)-Verbenone, a monoterpene bicyclic ketone, is a component of the essential oil from rosemary species such as Rosmarinus officinalis L., Verbena triphylla, and Eucalyptus globulus and is used for an herb tea, a spice, and a perfume. In this study, (؊)-verbenone was found to be converted to 10-hydroxyverbenone by rat and human liver microsomal cytochrome P450 (P450) enzymes. The product formation was determined by high-performance liquid chromatography with UV detection at 251 nm. There was a good correlation between activities of coumarin 7-hydroxylation and ( hydroxylation at all, suggesting that there were species-related differences in the catalytic properties of human and rat CYP2A enzymes in the metabolism of (؊)-verbenone. In the rat, recombinant CYP2C11, CYP2B1, and CYP3A2 catalyzed (؊)-verbenone 10-hydroxylation with V max and K m ratios (ml/min/nmol P450) of 0.73, 0.20, and 0.03, respectively. Male-specific CYP2C11 was a major enzyme in (؊)-verbenone 10-hydroxylation by untreated rat livers, and CYP2B1 catalyzed this reaction in liver microsomes of phenobarbital-treated rats. Rat CYP2C12, a female-specific enzyme, did not catalyze (؊)-verbenone 10-hydroxylation. These results suggest that human CYP2A6 and rat CYP2C11 are the major catalysts in the metabolism of (؊)-verbenone by liver microsomes and that there are speciesrelated differences in human and rat CYP2A enzymes and sex-related differences in male and female rats in the metabolism of (؊)-verbenone.

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Predicting the cytochrome P450 mediated metabolism of xenobiotics

Cited by 113 publications

References 0 publications

Activation of CYP2C9-Mediated Metabolism by a Series of Dapsone Analogs: Kinetics and Structural Requirements

Activation of CYP2C9-Mediated Metabolism by a Series of Dapsone Analogs: Kinetics and Structural Requirements

Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes.

Roles of Human Cyp2a6 and 2b6 and Rat Cyp2c11 and 2b1 in the 10-Hydroxylation of (–)-Verbenone by Liver Microsomes

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