Current Progress on Esterases: From Molecular Structure to Function

Satoh, Takaya; Taylor, Palmer; Bosron, William F.; Sanghani, Sonal P.; Hosokawa, Masakiyo; Du, Bert N. La

doi:10.1124/dmd.30.5.488

Cited by 276 publications

(251 citation statements)

References 36 publications

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“…Heart, liver, lung and kidney were the tissues that proved to be the least useful for the confirmation of heroin after death as at best only 1/3 of samples were positive for 6-MAM after death. These matrices have previously been shown to have high levels of carboxylesterase one of the enzymes responsible for the metabolism of 6-MAM [32]. 6-MAM in bone marrow appeared to be stable for between 30 minutes to 24 h with only 1/3 of samples positive at 24 h. These results suggest that 6-MAM is not as stable in rabbit bone marrow as other species (rats and human), where 6-MAM has been shown to be detectable up to 2 months after death.…”

Section: Detection Of 6-mam In Rabbit Tissuesmentioning

confidence: 99%

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h

Maskell

Albeishy²,

Paoli

et al. 2015

Int J Legal Med

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The interpretation of postmortem drug levels is complicated by changes in drug blood levels in the postmortem period, a phenomena known as postmortem drug redistribution. We investigated the postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in a rabbit model. Heroin (1mg/kg) was injected into anesthetised rabbit, after 1 hour an auricular vein blood sample was taken and the rabbit was euthanised. Following death rabbits were placed in a supine position at room temperature and divided into 3 groups namely 1) immediate autopsy, 2) autopsy after 30 minutes and 3) autopsy 24 h after death. Various samples which included femoral

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Section: Detection Of 6-mam In Rabbit Tissuesmentioning

confidence: 99%

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h

Maskell

Albeishy²,

Paoli

et al. 2015

Int J Legal Med

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“…For example, the preferential substrates for CES1A1, a human CES1 family isozyme, are thought to be compounds esterified by small alcohols, while those for CES2A1, a human CES2 family isozyme, are thought to be compounds esterified by relatively large alcohols. CES1A1, but not CES2A1, hydrolyzed the methyl ester of cocaine and the ethyl esters of temocapril, meperidine, imidapril and oseltamivir (Pindel et al, 1997;Takai et al, 1997;Mori et al, 1999;Satoh et al, 2002;Furihata et al, 2004a;Shi et al, 2006;Ose et al, 2009).…”

Section: Drug Metabolismmentioning

confidence: 99%

Carboxylesterases: Structure, Function and Polymorphism

Satoh¹,

Hosokawa²

2009

Biomolecules and Therapeutics

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-This review covers current developments in molecular-based studies of the structure and function of carboxylesterases. To allay the confusion of the classic classification of carboxylesterase isozymes, we have proposed a novel nomenclature and classification of mammalian carboxylesterases on the basis of molecular properties. In addition, mechanisms of regulation of gene expression of carboxylesterases by xenobiotics, and involvement of carboxylesterase in drug metabolism are also described.

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“…Enzymatic stability involving acyl-floxuridine esters has been studied in a limited manner using tissue homogenates containing esterase enzymes (3,15). Yet, the specific enzymes involved in the activation process of prodrugs have been rarely studied and have often been termed ubiquitous esterases and proteases (16,17). An esterase enzyme involved in the conversion of valacyclovir to its parent drug acyclovir has been identified and may be involved in the activation of other amino acid prodrugs (18).…”

Section: Introductionmentioning

confidence: 99%

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

Landowski

Vig

Song

et al. 2005

Molecular Cancer Therapeutics

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Floxuridine is a clinically proven anticancer agent in the treatment of metastatic colon carcinomas and hepatic metastases. However, prodrug strategies may be necessary to improve its physiochemical properties and selectivity and to reduce undesirable toxicity effects. Previous studies with amino acid ester prodrugs of nucleoside drugs targeted to the PEPT1 transporter coupled with recent findings of the functional expression of the PEPT1 oligopeptide transporter in pancreatic adenocarcinoma cell lines suggest the potential of PEPT1 as therapeutic targets for cancer treatment. In this report, we show the feasibility of achieving enhanced transport and selective antiproliferative action of amino acid ester prodrugs of floxuridine in cell systems overexpressing PEPT1. All prodrugs exhibited affinity for PEPT1 (IC 50 , 1.1 -2.3 mmol/L). However, only the prolyl and lysyl prodrugs exhibited enhanced uptake (2-to 8-fold) with HeLa/PEPT1 cells compared with HeLa cells, suggesting that the aspartyl prodrugs are PEPT1 inhibitors. The selective growth inhibition of Madine-Darby canine kidney (MDCK)/PEPT1 cells over MDCK cells by the prodrugs was consistent with the extent of their PEPT1-mediated transport. All ester prodrugs hydrolyzed to floxuridine fastest in Caco-2 cell and MDCK homogenates and slower in human plasma and were most chemically stable in pH 6.0 buffer. Prolyl and lysyl prodrugs were relatively less stable compared with aspartyl prodrugs in buffers and in cell homogenates. The results suggest that optimal design for targeted delivery would be possible by combining both stability and transport characteristics afforded by the promoiety. [Mol Cancer Ther 2005;4(4):659 -67]

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Current Progress on Esterases: From Molecular Structure to Function

Cited by 276 publications

References 36 publications

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h

Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h

Carboxylesterases: Structure, Function and Polymorphism

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

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