Nature and role of xenobiotic metabolizing esterases in rat liver, lung, skin and blood

McCracken, Nigel W.; Blain, PG; Williams, Faith M.

doi:10.1016/0006-2952(93)90373-5

Cited by 84 publications

(34 citation statements)

References 13 publications

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“…They are ubiquitously expressed in mammalian liver, blood, and extrahepatic tissues, including skin, kidney, intestines, testes, brain, central nervous system, and lung (Satoh and Hosokawa, 1998). Carboxylesterases (EC 3.1.1.1) are present in both the endoplasmic reticulum and cytosol (McCracken et al, 1993). The nature of microsomal esterases in human liver and gut have been most extensively studied (Huang et al, 1996) because of their role in hydrolyzing orally ingested drugs.…”

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confidence: 99%

“…The carboxylesterase inhibitors bis-nitrophenylphos- dmd.aspetjournals.org phate (BNPP; stock solution of 1 mM made up in DMSO) (Yoshigae et al, 1999), paraoxon (stock solution of 1 mM made up in ethanol) (Imai et al, 2003), and phenylmethylsulfonyl fluoride (PMSF; stock solution of 1 mM made up in DMSO) (Yoshigae et al, 1999) were added at a final concentration of 1 M. Additionally, to determine the presence of cholinesterases, the acetyl/butyryl cholinesterase inhibitor eserine (stock solution of 1 mM made up in DMSO) (Hewitt et al, 2000), the specific acetylcholinesterase inhibitor Bw284c51 (stock solution of 1 mM made up in water), and the specific butyrylcholinesterase inhibitor tetraisopropyl-pyrophosphoramide (IsoOMPA; stock solution of 1 mM made up in ethanol) were used at 1 M. Bw284c51 and IsoOMPA were shown to completely inhibit acetylcholinesterase and cholinesterase activity at 1 M (data not shown). To determine whether arylesterase (paraoxonase) contributed to the hydrolysis of ester substrates, mercuric chloride (stock solution of 1 mM made up in water), which completely inhibited arylesterase activity, was added at a final concentration 1 M (McCracken et al, 1993). All inhibitors were added to microsomes and cytosol fractions from human, minipig, and rat skin and liver in the presence of procaine, MUA, PV, PA, or NPA.…”

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confidence: 99%

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Specificity of Procaine and Ester Hydrolysis by Human, Minipig, and Rat Skin and Liver

Jewell

Ackermann²,

Payne³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The capacity of human, minipig, and rat skin and liver subcellular fractions to hydrolyze the anesthetic ester procaine was compared with carboxylesterase substrates 4-methylumbelliferyl-acetate, phenylvalerate, and para-nitrophenylacetate and the arylesterase substrate phenylacetate. Rates of procaine hydrolysis by minipig and human skin microsomal and cytosolic fractions were similar, with rat displaying higher activity. Loperamide inhibited procaine hydrolysis by human skin, suggesting involvement of human carboxylesterase hCE2. The esterase activity and inhibition profiles in the skin were similar for minipig and human, whereas rat had a higher capacity to metabolize esters and a different inhibition profile. Minipig and human liver and skin esterase activity was inhibited principally by paraoxon and bis-nitrophenyl phosphate, classical carboxylesterase inhibitors. Rat skin and liver esterase activity was inhibited additionally by phenylmethylsulfonyl fluoride and the arylesterase inhibitor mercuric chloride, indicating a different esterase profile. These results have highlighted the potential of skin to hydrolyze procaine following topical application, which possibly limits its pharmacological effect. Skin from minipig used as an animal model for assessing transdermal drug preparations had similar capacity to hydrolyze esters to human skin.

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confidence: 99%

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confidence: 99%

Specificity of Procaine and Ester Hydrolysis by Human, Minipig, and Rat Skin and Liver

Jewell

Ackermann²,

Payne³

et al. 2007

Drug Metab Dispos

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“…It is not merely a passive structural barrier between the body and environmental chemicals but also may be important site of metabolism. In recent years, although cutaneous metabolic reactions with skin preparations, tissue-cultured skin, and slices have been well studied, most of the work has dealt with oxidative reactions catalyzed by cytochrome P450 (Kao and Carver, 1990;Jugert et al, 1994;Ahmad et al, 1996;Cotovio et al, 1996) and alcohol dehydrogenase (Boehnlein et al, 1994); conjugative reactions catalyzed by glutathione S-transferase (Mukhtar and Bickers, 1981;Agarwal et al, 1992), UDP-glucuronosyltransferase (Moloney et al, 1982), and sulfotransferase (Wong et al, 1993); and hydrolytic reac- tions catalyzed by esterases (McCracken et al, 1993). Little is known about reductive reactions in skin.…”

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confidence: 99%

Xanthine Oxidase-Catalyzed Metabolism of 2-Nitrofluorene, a Carcinogenic Air Pollutant, in Rat Skin

Ueda¹,

Kawa²,

Ohashi³

et al. 2003

Drug Metab Dispos

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ABSTRACT:The reductive metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin microsomes and cytosol was investigated. 2-Nitrofluorene was reduced to the corresponding amine by the microsomes with NADPH and by the cytosol with 2-hydroxypyrimidine or 4-hydroxypyrimidine under anaerobic conditions. The cytosolic activity was much higher than that of skin microsomes. The 2-or 4-hydroxypyrimidine-linked nitroreductase activity was inhibited by oxypurinol and (؉/؊)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one (BOF-4272), inhibitors of xanthine oxidase, but not by menadione, chlorpromazine and isovanillin, inhibitors of aldehyde oxidase. When skin cytosol was applied to a DEAE-cellulose column, the fractions containing xanthine oxidase exhibited a marked 2-hydroxypyrimidine-linked nitroreductase activity. In contrast, the aldehyde oxidase fraction showed little activity. Nitroreductase fractions obtained by ion exchange chromatography showed a band in Western blotting analysis using anti-rat xanthine oxidase. Moreover, the xanthine oxidase fraction exhibited a significant nitroreductase activity in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine or hypoxanthine, and these activities were inhibited by inhibitors of xanthine oxidase. These results indicated that reduction of 2-nitrofluorene in the skin was mainly catalyzed by xanthine oxidase.

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“…[26][27][28] Generally, the hepatic esterase activity develops after birth and increases to the same activity as the adult level between the third and sixth weeks. 8,9) Although the amount of esterases in the liver were significantly higher (about 10-300 times) than those in the skin, 29) the tendency of the developmental process in the both esterase activities seems to be similar.…”

Section: Discussionmentioning

confidence: 95%

Age Difference in Simultaneous Permeation and Metabolism of Ethyl Nicotinate in Rat Skin.

Ngawhirunpat¹,

Hatanaka

Kawakami³

et al. 2001

Biological & Pharmaceutical Bulletin

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One of the most useful methods to enhance transdermal delivery of drugs is utilization of lipophilic prodrugs.1,2) Prodrug modification by esterification is quite common among topical pharmaceuticals commercialized in the market, because the dominant dermal enzymes responsible for biotransformation are esterases.3) Ester prodrugs for topical application can be metabolized by dermal esterases into active forms, therefore, those prodrugs should be metabolized completely in the skin layer to maximize topical therapeutic activity and to minimize both topical and systemic adverse effects.Structural changes in the skin are related to age, 4,5) nevertheless, it has not been clarified whether or not the development of dermal esterase activity is also associated with age. Some researchers have reported that hepatic esterase enzymes in full-term newborns of mammalian species are lower than those in adults, 6,7) and the activity of hepatic esterases develops after birth and increases to the adult level through the growth process. 8,9) Although the effects of skin metabolism on the transdermal permeability of prodrugs have been investigated, 10,11) no data is available for age discrepancy of simultaneous transport and metabolism by skin esterase enzymes. Therefore, it is of great importance to study this knowledge as it can be applied to estimate the transdermal administration of prodrugs for different age populations.The present study focused on age differences in simultaneous skin transport and metabolism. Ethyl nicotinate (EN) was selected as a model prodrug of nicotinic acid (NA). In vitro skin permeation characteristics and enzyme activity in skin homogenate were compared using various ages of rats. Finally, we clarified the development of dermal esterases in the growth process. MATERIALS AND METHODSMaterials NA and EN were purchased from Tokyo Chemical Industries (Tokyo, Japan). All other reagents and solvents were commercially available and of analytical grade.Animals Male STD: Wistar rats at the ages of a fetus at 21 d, 3, 10, 50, 270 and 360 d (Japan SLC, Inc., Hamamatsu, Japan) were used. Rats were fed commercial food pellets and tap water ad libitum. A round section of abdominal skin was freshly excised under sodium pentobarbital anesthesia (50 mg/kg, i.p.) after being shaved carefully. The full-thickness skin of rats at different ages was used as a membrane for the skin transport and skin homogenate experiment, however, the esterase activity is higher in epidermis than dermis. 12,13) Therefore, variation in thickness of dermis at different ages may not be significant.Skin Transport Experiment The skin samples were mounted between two half cells of a side-by-side diffusion chamber 14) (3.0 ml volume and 0.966 cm 2 effective diffusion area) with a water-jacket connected to a water bath at 37°C. The receiver and donor compartments were filled with 0.1 M phosphate buffered saline pH 7.4 (PBS) and stirred at 1440 rpm with a star-head Teflon ® magnetic bar (Nalge Nunc International Co., Ltd., Minnesota, U.S.A.) driven...

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Nature and role of xenobiotic metabolizing esterases in rat liver, lung, skin and blood

Cited by 84 publications

References 13 publications

Specificity of Procaine and Ester Hydrolysis by Human, Minipig, and Rat Skin and Liver

Specificity of Procaine and Ester Hydrolysis by Human, Minipig, and Rat Skin and Liver

Xanthine Oxidase-Catalyzed Metabolism of 2-Nitrofluorene, a Carcinogenic Air Pollutant, in Rat Skin

Age Difference in Simultaneous Permeation and Metabolism of Ethyl Nicotinate in Rat Skin.

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