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

Yin, Huadong; Anders, M. W.; Korzekwa, Kenneth R.; Higgins, Lee Ann; Thummel, Kenneth E.; Kharasch, Evan D.; Jones, Jeffrey P.

doi:10.1073/pnas.92.24.11076

Cited by 67 publications

(42 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most of these substrates are small and hydrophobic. They include alcohols/ketones/ aldehydes, aromatic compounds, halogenated alkanes or alkenes, anaesthetics, drugs, and premutagens such nitrosamines (found in cigarette smoke) and azo carcinogens (153)(154)(155)(156). Many of the CYP2E1 substrates are also inducers of the enzyme.…”

Section: Cyp2e1mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

160

111

View full text Add to dashboard Cite

The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

show abstract

Section: Cyp2e1mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

160

111

View full text Add to dashboard Cite

show abstract

“…The required diversity is accomplished by families and subfamilies of enzymes with generally broad substrate specificities, a very reactive oxygenating species and a broad regioselectivity. Thus, for many reactions, the electronic features of the substrate are all that are required to predict regioselectivity (Grogan et al, 1992;Harris et al, 1992;de Groot et al, 1995de Groot et al, , 1999Yin et al, 1995).…”

Section: The P450mentioning

confidence: 99%

“…This model has been successfully used to predict the rates of metabolism of halogenated hydrocarbons (Harris et al, 1992;Yin et al, 1995) and the regioselectivity of nitrile metabolism (Grogan et al, 1992) both in vivo and in vitro. In this article, we report the development of a model for aromatic oxidation and the combination of this model with our previous model for hydrogen atom abstraction.…”

mentioning

confidence: 99%

Computational Models for Cytochrome P450: A Predictive Electronic Model for Aromatic Oxidation and Hydrogen Atom Abstraction

Jones¹,

Mysinger²,

Korzekwa³

2002

Drug Metab Dispos

119

132

View full text Add to dashboard Cite

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Experimental observations suggest that electronic characteristics play a role in the rates of substrate oxidation for cytochrome P450 enzymes. For example, the tendency for oxidation of a certain functional group generally follows the relative stability of the radicals that are formed (e.g., N-dealkylation > O-dealkylation > 2°c arbon oxidation > 1°carbon oxidation). In addition, results show that useful correlations between the rates of product formation can be developed using electronic models. In this article, we attempt to determine whether a combined computational model for aromatic and aliphatic hydroxylation can be developed. Toward this goal, we used a combination of experimental data and semiempirical molecular orbital calculations to predicted activation energies for aromatic and aliphatic hydroxylation. The resulting model extends the predictive capacity of our previous aliphatic hydroxylation model to include the second most important group of oxidations, aromatic hydroxylation. The combined model can account for about 83% of the variance in the data for the 20 compounds in the training set and has an error of about 0.7 kcal/mol. The P4501 enzymes are a superfamily of monooxygenases involved in the metabolism of both exogenous and endogenous compounds. Ironically, these enzymes play a central role in both the prevention and induction of chemical toxicities and carcinogenicity. Although most P450 oxidations of xenobiotics result in detoxification, occasionally a more toxic intermediate is formed. In fact, many ultimate toxins and carcinogens are formed by the bioactivation of less reactive compounds, and many bioactivation reactions are mediated by the P450 enzymes. Often bioactivation reactions are in competition with detoxification pathways for the same substrate. Since these enzymes play such a central role in both detoxification and bioactivation, predictive models for cytochrome P450 catalysis will be useful tools for evaluating of the potential risks of environmental exposures. One of the most pertinent but difficult problems in risk assessment is translating bench results and mechanistic information into a form that can be used. This article outlines steps toward the development of computational models from laboratory data into a form that can be used for risk assessments that accurately reflect experimental results. For example, these models now more completely describe all positions of metabolism for nitriles and should be more complete in predicting the toxicity related to nitrile metabolism. These semiempirical computational models blend experimental data and computational chemistry in such a way as to provide a consistent prediction of the bioactivation rates for a broad spectrum of compounds. In particular, these models can be used to predict xenobiotic metabolism by the P450 enzyme family, including the bioactivation of compounds to toxins and carcinogens.Models such as those presented here for P450-mediated reaction...

show abstract

“…The hydroxylated product formed by recombination may rearrange to yield more stable products. Inherent differences in the reactivity of substrate atoms (Korzekwa et al, 1990;Yin et al, 1995;Jones et al, 2002) and the probability for close proximity of the atom to the reactive intermediate are also determinants of sites and rates of reaction (Cruciani et al, 2005). The presence of the substrate in close proximity to the heme iron can influence rates of reduction and reduce the formation of alternative products of oxygen reduction (Sligar, 1976).…”

Section: Introductionmentioning

confidence: 99%

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

et al. 2013

View full text Add to dashboard Cite

This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drugmetabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b 5 . Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b 5 and P450 surfaces, showing that b 5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b 5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

show abstract

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

Cited by 67 publications

References 32 publications

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Computational Models for Cytochrome P450: A Predictive Electronic Model for Aromatic Oxidation and Hydrogen Atom Abstraction

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

Contact Info

Product

Resources

About