Inhibition of Carboxylesterases by Benzil (Diphenylethane-1,2-dione) and Heterocyclic Analogues Is Dependent upon the Aromaticity of the Ring and the Flexibility of the Dione Moiety

Hyatt, Janice L.; Stacy, Vanessa; Wadkins, Randy M.; Yoon, Karina J.; Wierdl, Monika; Edwards, Carol C.; Zeller, Mat­thias; Hunter, Allen D.; Danks, Mary K.; Crundwell, Guy; Potter, Philip M.

doi:10.1021/jm0504196

Cited by 61 publications

(69 citation statements)

References 30 publications

(76 reference statements)

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“…By using these proteins, inhibitors that selectively target specific CE isozymes have been developed [54,55]. These reagents have been and will continue to be of value for studying the hydrolytic metabolism of environmental contaminants, e.g.…”

Section: Future Outlookmentioning

confidence: 99%

Human carboxylesterases and their role in xenobiotic and endobiotic metabolism

Ross

Crow

2007

J Biochem & Molecular Tox

149

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Carboxylesterases (CEs) are traditionally regarded as xenobiotic metabolizing enzymes that hydrolyze esterified xenobiotics to alcohol and carboxylic acid products. However, there is a growing appreciation for the role of CEs in the processing of endobiotics, including cholesteryl esters and triacylglycerols. Human liver microsomes (HLMs) are often used in reaction phenotyping studies to discern interindividual variability in xenobiotic metabolism. The two major CE isoforms expressed in human liver are hCE1 and hCE2. These two isoforms are different gene products. We have begun studies to evaluate the CE phenotype'' of human liver samples, i.e. to determine both the levels of hCE1 and hCE2 protein and the hydrolytic activity of each. We have previously shown that there is little variation in hCE1 protein expression in HLM samples from 11 individuals [a 1.3-fold difference between the highest and lowest individuals; coefficient of variation (CV), 9%]. hCE2 protein expression in individual HLMs is only slightly more variable than hCE1 (2.3-fold difference between the highest and lowest individuals; CV, 36%). However, hCE1 protein is found in 46-fold higher amounts in HLMs than hCE2 protein (64.4 +/- 16.5 microg hCE1/mg microsomal protein compared to 1.4 +/- 0.2 microg hCE2/mg microsomal protein). The hydrolytic activity specifically attributable to hCE1 and hCE2 in individual HLMs was measured using bioresmethrin (a pyrethroid insecticide hydrolyzed specifically by hCE1, but not by hCE2) and procaine (an analgesic drug hydrolyzed by hCE2, but not by hCE1). The hydrolytic activity of individual HLMs toward bioresmethrin and procaine did not correlate with the protein content of hCE1 and hCE2. Thus, the mere abundance of CE proteins is not a good predictor of CE activity in HLMs. Identification of the factors that lead to altered CE activities in HLMs will be important to characterize since several pharmaceutical agents, environmental toxicants, and endobiotics are metabolized by these enzymes.

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Section: Future Outlookmentioning

confidence: 99%

Human carboxylesterases and their role in xenobiotic and endobiotic metabolism

Ross

Crow

2007

J Biochem & Molecular Tox

149

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“…Furthermore, using a series of heteroaromatic derivatives, it was noted that the potency of CE inhibition was related to the 'aromaticity' of the ring [43]. For example, the naphthyl derivate was much more potent at inhibiting rCE (K i = 1nM) as compared to benzil (K i = 103nM), or the furyl compound (K i = 8,480nM).…”

Section: Benzilmentioning

confidence: 99%

Carboxylesterases - Detoxifying Enzymes and Targets for Drug Therapy

Potter¹,

Wadkins²

2006

CMC

135

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Carboxylesterases (CE) are ubiquitous enzymes responsible for the detoxification of xenobiotics. Many therapeutically useful drugs are metabolized by these proteins which impacts upon the efficiency of drug treatment. In some instances, CEs convert inactive prodrugs to active metabolites, a process that is essential for biological activity. Such compounds include the anticancer agents CPT-11 (3) and capecitabine (4), the antibiotics Ceftin (9) and Vantin, as well as the illicit street drug heroin (6). However, more commonly, CEs hydrolyze many esterified drugs to inactive products that are then excreted. Agents such as flestolol (11), meperidine (5), lidocaine (8) and cocaine (7), are all hydrolyzed and inactivated by these enzymes. Therefore the efficacy of esterified drugs will be dependent upon the distribution and catalytic activity of different CEs. In this review, we examine the structural aspects of CEs and their roles in drug detoxification and propose that modulation of CE activity may allow for improvements in, and potentiation of, drug efficacy.

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“…Because all of the selective carboxylesterase inhibitors that have been recently identified act in a reversible fashion (25,26,31), a novel in situ assay was required to ensure that enzyme inhibition was occurring intracellularly. This was necessary because, during the preparation of cell extracts to measure carboxylesterase activity, the concentration of inhibitor would be vastly diluted, and hence, inhibition of carboxylesterase would not be apparent.…”

Section: Development Of An In Vivo Carboxylesterase Activity Assaymentioning

confidence: 99%

Intracellular inhibition of carboxylesterases by benzil: modulation of CPT-11 cytotoxicity

Hyatt

Tsurkan

Wierdl

et al. 2006

Molecular Cancer Therapeutics

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Carboxylesterases are ubiquitous proteins responsible for the detoxification of xenobiotics. However, these enzymes also activate prodrugs, such as the anticancer agents capecitabine and CPT-11. As a consequence, overexpression of carboxylesterases within tumor cells sensitizes these cells to CPT-11. We have recently identified two classes of carboxylesterase inhibitors based on either a benzil (diphenylethane-1,2-dione) or a benzene sulfonamide scaffold and showed that these compounds inhibit carboxylesterases with K i s in the low nanomolar range. Because both classes of inhibitors show reversible enzyme inhibition, conventional in vitro biochemical assays would not accurately reflect the in situ levels of carboxylesterase activity or inhibition. Therefore, we have developed a novel assay for the determination of intracellular carboxylesterase activity using 4-methylumbelliferone as a substrate. These studies show that benzil and a dimethylbenzil analogue efficiently enter cells and inhibit human intestinal carboxylesterase and rabbit liver carboxylesterase intracellularly. This inhibition results in reduced cytotoxicity to CPT-11 due to the lack of carboxylesterase-mediated conversion of the prodrug to SN-38. These results suggest that intracellular modulation of carboxylesterase activity with benzil or its analogues may be applied to minimize the toxicity of normal cells to

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Inhibition of Carboxylesterases by Benzil (Diphenylethane-1,2-dione) and Heterocyclic Analogues Is Dependent upon the Aromaticity of the Ring and the Flexibility of the Dione Moiety

Cited by 61 publications

References 30 publications

Human carboxylesterases and their role in xenobiotic and endobiotic metabolism

Human carboxylesterases and their role in xenobiotic and endobiotic metabolism

Carboxylesterases - Detoxifying Enzymes and Targets for Drug Therapy

Intracellular inhibition of carboxylesterases by benzil: modulation of CPT-11 cytotoxicity

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