Subcellular localization of non-specific carboxylesterases, acylcarnitine hydrolase, monoacylglycerol lipase and palmitoyl-CoA hydrolase in rat liver

Mentlein, Rolf; Rix-Matzen, Hella; Heymann, Eberhard

doi:10.1016/0304-4165(88)90032-3

Cited by 62 publications

(34 citation statements)

References 39 publications

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“…Recently, Quinney et al (2005) reported that loperamide, an opioid compound, competitively inhibited CES, especially human CES2 isozyme, hCE2, with a K i of 1.5 M. However, the effect of loperamide on the activity of other hydrolases is not mentioned in detail, and reduction of gastrointestinal motility by loperamide might affect drug absorption in other ways (Callreus et al, 1999). On the other hand, BNPP is well known as a potent and specific inhibitor of CES isozymes (Heymann and Krisch, 1967;Block and Arndt, 1978;Mentlein et al, 1988). We first determined that BNPP noncompetitively inhibited PNPA hydrolysis in the rat jejunal S9 with a K i value of 44.9 Ϯ 4.95 nM.…”

Section: Discussionmentioning

confidence: 99%

“…BNPP specifically combines with CES and suppresses hydrolase activity by noncompetitive inhibition without any modulation of ␣-chymotrypsin, trypsin, acetylcholinesterase, or nonspecific serum cholinesterase (Heymann and Krisch, 1967;Block and Arndt, 1978;Mentlein et al, 1988). In addition, we investigated the hydrolyzing capacity and expression level of rat intestinal CES isozymes in the jejunum and the ileum.…”

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Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Masaki¹,

Hashimoto²,

Imai³

2007

Drug Metab Dispos

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ABSTRACT:To determine the activity of a major intestinal esterase in the first-pass hydrolysis of O-isovaleryl-propranolol (isovaleryl-PL), a model ester compound, rat intestinal jejunum and blood vessels were perfused simultaneously after inhibition of a carboxylesterase (CES) by bis-p-nitrophenyl phosphate (BNPP). BNPP specifically inhibits approximately 90% of CES activity without influencing aminopeptidase activity or the transport of L-leucyl-p-nitroanilide and p-nitroaniline, nonester compounds. When isovaleryl-PL was perfused into the jejunal lumen after BNPP treatment, its absorption clearance (7.60 ؎ 0.74 l/min) increased approximately 3-fold compared with control, whereas its degradation clearance (32.5 ؎ 5.40 l/min) decreased to 23% of control. Therefore, CES seems to be mainly responsible for the intestinal first-pass hydrolysis of isovaleryl-PL. This finding is consistent with the results from studies of in vitro BNPP inhibition in the mucosal S9 fraction. V max values for valeryl-PL, isovaleryl-PL, and p-nitrophenyl acetate in the jejunal S9 fraction were 1.7-to 2.5-fold higher than that in the ileal S9 fraction, which agreed with the jejunum/ileum ratio (approximately 1.5-fold) of mRNA expression levels for the CES2 isozymes, AB010635 and AY034877. These findings indicated that CESs expressed in the intestine markedly contribute to first-pass hydrolysis in both jejunum and ileum.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Masaki¹,

Hashimoto²,

Imai³

2007

Drug Metab Dispos

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“…After the desired incubation time at 37°C, the basolateral solution was collected and replaced with an equal volume of HBSS. To investigate the effect of esterase inhibitor treatment of Caco-2 cells on the permeability of oseltamivir in the apical-to-basolateral direction, Caco-2 cells were preincubated with 200 M BNPP, a specific carboxylesterase inhibitor (Block and Arndt, 1978;Mentlein et al, 1988) at 37°C for 45 min. We also examined the influence of permeability of oseltamivir across a Caco-2 cell monolayer in the presence of 10 M verapamil, an inhibitor of P-gp (Ogihara et al, 2004).…”

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Oseltamivir (Tamiflu) Is a Substrate of Peptide Transporter 1

Ogihara¹,

Kano²,

Wagatsuma³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Oseltamivir, an ester-type prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), has been developed for the treatment of A and B strains of the influenza virus but has neuropsychiatric and other side effects. In this study, we characterized the transport across intestinal epithelial cells and the absorption of oseltamivir in rats. Uptake by Caco-2 cells (human carcinoma cell line) and HeLa cells transfected with peptide transporter 1 (HeLa/ PEPT1) was time-and temperature-dependent and was inhibited by typical PEPT1 inhibitors such as glycyl-sarcosine (Gly-Sar). The uptake by Caco-2 cells and HeLa/PEPT1 was saturable, with similar K m values. Oseltamivir absorption in adult rats was greatly reduced by simultaneous administration of milk, casein, or Gly-Sar. Furthermore, the plasma and brain concentrations of oseltamivir were higher in fasting than in nonfasting rats after oral administration. These results suggest that oseltamivir is a substrate of PEPT1 and that PEPT1 is involved in its intestinal absorption.Various transporters are expressed on apical and basolateral membranes of intestinal epithelial cells, serving to take up nutrients and to excrete xenobiotics into the lumen. Influx transporters are able to accept nutrients and also various drugs as substrates. In particular, peptide transporter 1 (PEPT1, SLC15A1), localized at brush-border membranes of human small intestine (Saito et al., 1995), plays important roles in the absorption of not only di-/tripeptides (Tamai et al., 1994) but also peptide-mimetic compounds, such as orally administered ␤-lactam antibiotics (Ganapathy et al., 1995;Sai et al., 1996) and the anticancer agent bestatin (Tomita et al., 1990;Inui et al., 1992). Several researchers recently found that intestinal PEPT1 can transport L-valine ester prodrugs, such as valacyclovir and valganciclovir (Balimane et al., 1998;Han et al., 1998;Sugawara et al., 2000). Therefore, such structural modification of drugs may result in increased intestinal absorption, mediated by PEPT1.Oseltamivir phosphate (oseltamivir), manufactured under the trade name Tamiflu as an ester-type prodrug of the neuraminidase inhibitor Ro 64-0802, has been developed for the treatment of A and B strains of the influenza virus. This drug has been reported to be associated with neuropsychiatric side effects (http://www.fda.gov/cder/drug/ infopage/tamiflu/QA20051117.htm and http://www.mhlw.go.jp/ english/index.html), which are likely to be caused by distribution of oseltamivir and/or its metabolite(s) to the central nervous system. We recently examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance (or resistant) 1 (MDR1) P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice (Morimoto et al., 2008). The permeability of oseltamivir in the basolateral-to-apical dire...

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“…However, since these two GEH forms did not exhibit any interfacial activation, it was suggested that the corresponding proteins could not belong to the lipase family [4]. Recently, a number of intracellular carboxylesterases were found to act as lipases and to efficiently hydrolyse monoacyl, diacyl and triacylglycerols, suggesting that they could be involved in the transport of fatty acids across the endoplasmic reticulum [5,6].…”

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Purification and molecular cloning of porcine intestinal glycerol‐ester hydrolase

David

Guo

Villard

et al. 1998

European Journal of Biochemistry

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A glycerol-ester hydrolase was purified to homogeneity from porcine intestinal mucosa using a partial delipidation method and an eight-step purification procedure. The isolation scheme used gave a 483-fold purification, resulting in a pure enzyme with a specific activity on tributyrin of 290 µmol · min Ϫ1 · mg Ϫ1 . The molecular mass of the enzyme was estimated at 240 kDa, based on the results of size-exclusion chromatography, and at 60 kDa, as determined by SDS/PAGE analysis. The isoelectric focusing data obtained indicated that only one isoform with a pI of 5.1 was present. Complete identity was found to exist between the N-terminal sequence of the first 25 amino acid residues and that of a porcine liver carboxylesterase. A full-length cDNA coding for the enzyme was isolated from pig small intestine. We observed that the corresponding protein originally named intestinal glycerol-ester hydrolase definitely belongs to the carboxylesterase family. The deduced amino acid sequence consisted of 565 residues and showed 97% identity with that of porcine liver carboxylesterase and more than 50% identity with those of other carboxylesterases from different mammalian species.

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Subcellular localization of non-specific carboxylesterases, acylcarnitine hydrolase, monoacylglycerol lipase and palmitoyl-CoA hydrolase in rat liver

Cited by 62 publications

References 39 publications

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

Oseltamivir (Tamiflu) Is a Substrate of Peptide Transporter 1

Purification and molecular cloning of porcine intestinal glycerol‐ester hydrolase

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