Mechanistic studies of uridine diphosphate glucuronosyltransferase

Yin, Huadong; Bennett, G. A.; Jones, Jeffrey P.

doi:10.1016/0009-2797(94)90110-4

Cited by 50 publications

(36 citation statements)

References 25 publications

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“…This result may suggest that under these conditions, other glucuronosyltransferases may participate in the glucuronidation of BPA. It is also possible that this high concentration of UDPGA could promote nonenzymatic glucuronidation of BPA by a bimolecular nucleophilic substitution reaction (Yin et al, 1994). The relative result of incubating HCs with exogenous UDPGA was an increase in CL int .…”

Section: Discussionmentioning

confidence: 99%

Prediction of Metabolic Clearance of Bisphenol A (4,4 ′-Dihydroxy-2,2-diphenylpropane) using Cryopreserved Human Hepatocytes

Kuester¹,

Sipes²

2007

Drug Metabolism and Disposition

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Section: Discussionmentioning

confidence: 99%

Prediction of Metabolic Clearance of Bisphenol A (4,4 ′-Dihydroxy-2,2-diphenylpropane) using Cryopreserved Human Hepatocytes

Kuester¹,

Sipes²

2007

Drug Metabolism and Disposition

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“…However, for bulky molecules, such as benzo-[a]pyrene and nicotine (38), the spatial interaction between the substrate and the apoprotein becomes significant and steric factors, in addition to electronic factors, influence the rate. Lipophilicity is a common parameter used in structureactivity relationships (39,40). CYPs, in general, prefer lipophilic substrates.…”

mentioning

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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“…Kinetic constants for simple phenolic substrate glucuronidation were modeled by QSAR to characterize a partially purified rat UGT (Yin et al, 1994).…”

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confidence: 99%

Quantitative Structure Activity Relationships for the Glucuronidation of Simple Phenols by Expressed Human UGT1A6 and UGT1A9

Ethell¹,

Ekins²,

Wang³

et al. 2002

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:UGT1A6 and UGT1A9 have both been demonstrated to rapidly glucuronidate simple phenolic compounds. A series of simple phenols were selected and screened with both isoforms and then used as model substrates for the generation of V max and K m values. UGT1A6 showed a more restricted acceptance of phenolic substrates compared with UGT1A9. However, the affinity of UGT1A6 for these compounds exhibited higher K m values than UGT1A9, although rates of turnover were similar. Molecular surfaceweighted holistic invariant molecular descriptors were generated for each substrate and used to produce the first quantitative structure activity relationship models generated for expressed human UGTs. Models relating log of the K m value to the generated descriptors correlated well with the experimental data r 2 value of

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Mechanistic studies of uridine diphosphate glucuronosyltransferase

Cited by 50 publications

References 25 publications

Prediction of Metabolic Clearance of Bisphenol A (4,4 ′-Dihydroxy-2,2-diphenylpropane) using Cryopreserved Human Hepatocytes

Prediction of Metabolic Clearance of Bisphenol A (4,4 ′-Dihydroxy-2,2-diphenylpropane) using Cryopreserved Human Hepatocytes

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

Quantitative Structure Activity Relationships for the Glucuronidation of Simple Phenols by Expressed Human UGT1A6 and UGT1A9

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