HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-<i>N</i>-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO] CARBONYLOXYCAMPTOTHECIN AND 7-ETHYL-10-[4-(1-PIPERIDINO)-1-AMINO]-CARBONYLOXYCAMPTOTHECIN, BY HUMAN CARBOXYLESTERASES CES1A1, CES2, AND A NEWLY EXPRESSED CARBOXYLESTERASE ISOENZYME, CES3

Sanghani, Sonal P.; Quinney, Sara K.; Fredenburg, Tyler B.; Davis, Wilhelmina I.; Murry, Daryl J.; Bosron, William F.

doi:10.1124/dmd.32.5.505

Cited by 122 publications

(74 citation statements)

References 17 publications

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“…These results are similar to previous expression studies of human carboxylesterase genes in insect cells [20].…”

Section: Preparation Of Recombinant Human Carboxylesterasessupporting

confidence: 92%

“…The average yield of each of the two recombinant enzymes in this study was around 2.5 mg from one liter of insect cell culture (Table 1). Purification coefficients between 40 and 50 were regularly obtained, indicating that the recombinant enzymes represent around 2% of the total cell protein.These results are similar to previous expression studies of human carboxylesterase genes in insect cells [20]. …”

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confidence: 92%

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Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2

Nishi

Huang

Kamita

et al. 2006

Archives of Biochemistry and Biophysics

104

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Carboxylesterases hydrolyze a large array of endogenous and exogenous ester-containing compounds, including pyrethroid insecticides. Herein, we report the specific activities and kinetic parameters of human carboxylesterase (hCE)-1 and hCE-2 using authentic pyrethroids and pyrethroid-like, fluorescent surrogates. Both hCE-1 and hCE-2 hydrolyzed type I and II pyrethroids with strong stereoselectivity. For example, the trans-isomers of permethrin and cypermethrin were hydrolyzed much faster than corresponding cis-counterparts by both enzymes. Kinetic values of hCE-1 and hCE-2 were determined using cypermethrin and 11 stereoisomers of the pyrethroid-like, fluorescent surrogates. K m values for the authentic pyrethroids and fluorescent surrogates were in general lower than those for other ester-containing substrates of hCEs. The pyrethroid-like, fluorescent surrogates were hydrolyzed at rates similar to the authentic pyrethroids by both enzymes, suggesting the potential of these compounds as tools for high throughput screening of esterases that hydrolyze pyrethroids. KeywordsCarboxylesterase; Pyrethroid; Fluorescent substrate Synthetic pyrethroid insecticides represented about 17% of the global pesticide market in 2002 [1]. In the coming years, the use of pyrethroids is predicted to further increase with the phase out of the use of organophosphorus insecticides. Additionally, due to the emergence and reemergence of mosquito-vectored diseases such as West Nile fever, Japanese encephalitis, and dengue fever, pyrethroids are being used with increased frequency against adult mosquitoes * Corresponding author. Fax: +1 530 752 1537.E-mail address: bdhammock@ucdavis.edu (B.D. Hammock). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [2]. Because of the increased agricultural and residential usage of pyrethroids, human exposure to these compounds is also expected to increase.Pyrethroids are ester-containing compounds consisting of various acid and alcohol moieties. Type I pyrethroids are esters of primary alcohols, whereas type II pyrethroids are esters of secondary alcohols that contain a cyano group at the α-carbon of the alcohol moiety. Chiral centers can exist in both the acid and alcohol moieties, leading to the existence of several stereoisomers for each pyrethroid. Ester hydrolysis by carboxylesterases and oxidation by cytochrome P450s are the main detoxification routes of pyrethroids in animals [3]. Differences in the activities of carboxylesterases and P450s between mammals and insects contribute to the low mammalian toxicity of pyrethroids (i.e., pyrethroids are metabolized faster in mammals than in insects) [3]. In general, whole animals or liver microsomes have been used to study pyrethroid metabolism in mammals, and little has been done to identify the specific carboxylesterase isozymes that hydrolyze pyrethroids [4]. Butte and Kemper [5]have shown ester-hydrolytic activities in human serum using pyrethroid-like colorimetric substrates that are not hydrolyzed by acylesterase, ...

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“…These results are similar to previous expression studies of human carboxylesterase genes in insect cells [20].…”

Section: Preparation Of Recombinant Human Carboxylesterasessupporting

confidence: 92%

supporting

confidence: 92%

Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2

Nishi

Huang

Kamita

et al. 2006

Archives of Biochemistry and Biophysics

104

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“…CarbEs are categorized as phase 1 drug metabolizing enzymes that can hydrolyze a variety of ester-containing drugs and prodrugs. These include angiotensin-converting enzyme (ACE) inhibitors (temocapril, cilazapril, quinapril, and imidapril) (Takai et al, 1997;Mori et al, 1999;Furihata et al, 2004a;Geshi et al, 2005), anti-tumor drugs (CPT-11 and capecitabin) Danks et al, 1998;Guichard et al, 1998;Kojima et al, 1998;Humerickhouse et al, 2000;Sanghani et al, 2004;Tabata et al, 2004), and narcotics (cocaine, heroin and meperidine) (Kamendulis et al, 1996;Zhang et al, 1999). Thus, CarbEs are one of the most important enzymes involved in prodrug activation notably with respect to tissue distribution, up-regulation in tumor cells and turnover rates.…”

Section: Drug Metabolismmentioning

confidence: 99%

“…CES3 includes ES-male (CES3A2) and human CES3 (CES3A1) (Aida et al, 1993;Sanghani et al, 2004). Human CES3 (CES3A1) has about 40% amino acid sequence identity with both CEA1A1 and CES2A1, and is expressed in the liver and gastrointestinal tract at an extremely low level in comparison with CES1A1 and CES2A1 (Sanghani et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…It includes human intestinal CarbE (CES2A1) (Schwer et al, 1997;Humerickhouse et al, 2000;Imai et al, 2006;Taketani et al, 2007;Yang et al, 2007;Shi et al, 2008), rCES2 (CES2A10) (Furihata et al, 2005), rat intestinal CarbE RL4 (rCES2) (CES2A6) (Furihata et al, 2003), rabbit form 2 (Ozols, 1989) and hamster AT51 (CES2A11) (Sone et al, 1994). CES3 includes ES-male (CES3A2) and human CES3 (CES3A1) (Aida et al, 1993;Sanghani et al, 2004). Human CES3 (CES3A1) has about 40% amino acid sequence identity with both CEA1A1 and CES2A1, and is expressed in the liver and gastrointestinal tract at an extremely low level in comparison with CES1A1 and CES2A1 (Sanghani et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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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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Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO] CARBONYLOXYCAMPTOTHECIN AND 7-ETHYL-10-[4-(1-PIPERIDINO)-1-AMINO]-CARBONYLOXYCAMPTOTHECIN, BY HUMAN CARBOXYLESTERASES CES1A1, CES2, AND A NEWLY EXPRESSED CARBOXYLESTERASE ISOENZYME, CES3

Cited by 122 publications

References 17 publications

Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2

Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2

Carboxylesterases: Structure, Function and Polymorphism

Retrometabolism‐Based Drug Design and Targeting

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