Hydrolytic Enzymes

Yan, Bingfang

doi:10.1002/9783527630905.ch6

Cited by 9 publications

(18 citation statements)

References 117 publications

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“…This study was undertaken to determine whether the two-phase developmental regulation represents a common phenomenon among drug-metabolizing enzymes in humans. This study focused on CES2 and CYP3A4, two major drug-metabolizing enzymes (Yan, 2012). CES2 and CYP3A4 share many substrates and their metabolism may have different clinical consequences (Smith et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

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Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation

et al. 2015

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Human carboxylesterase-2 (CES2) and cytochrome P450 3A4 (CYP3A4) are two major drug metabolizing enzymes that play critical roles in hydrolytic and oxidative biotransformation, respectively. They share substrates but may have opposite effect on therapeutic potential such as the metabolism of the anticancer prodrug irinotecan. Both CES2 and CYP3A4 are expressed in the liver and the gastrointestinal tract. This study was conducted to determine whether CES2 and CYP3A4 are expressed under developmental regulation and whether the regulation occurs differentially between the liver and duodenum. A large number of tissues (112) were collected with majority of them from donors at 1-198 days of age. In addition, multi-sampling (liver, duodenum and jejunum) was performed in some donors. The expression was determined at mRNA and protein levels. In the liver, CES2 and CYP3A4 mRNA exhibited a postnatal surge (1 versus 2 months of age) by 2.7 and 29 fold, respectively. CYP3A4 but not CES2 mRNA in certain pediatric groups reached or even exceeded the adult level. The duodenal samples, on the other hand, showed a gene-specific expression pattern at mRNA level. CES2 mRNA increased with age but the opposite was true with CYP3A4 mRNA. The levels of CES2 and CYP3A4 protein, on the other hand, increased with age in both liver and duodenum. The multi-sampling study demonstrated significant correlation of CES2 expression between the duodenum and jejunum. However, neither duodenal nor jejunal expression correlated with hepatic expression of CES2. These findings establish that developmental regulation occurs in a gene and organ-dependent manner.

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Section: Resultsmentioning

confidence: 99%

“…This study focused on CES2 and cytochrome P450 3A4 (CYP3A4). In humans, CES1 and CES2 together represent as much as 90% of hydrolytic capacity toward drugs and other xenobiotics (Yan, 2012; Sanghani et al, 2009). CYP3A4 is a member of the cytochrome P450 mixed-function oxidase system (Klein and Zanger, 2013).…”

Section: Introductionmentioning

confidence: 99%

Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation

et al. 2015

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“…It was unexpected that mouse microsomes shared with human but not rat microsomes in terms of the inhibition profile, although mouse and rat share more similarities in terms of the tissue distribution of CESs and the number of CES genes (17). We did not have all human and rodent CESs in purified form or in expression construct.…”

Section: Resultsmentioning

confidence: 99%

“…While CESs hydrolyze drugs and other xenobiotics, some CESs hydrolyze lipids as well (14, 15). In the human genome, seven CES genes exist with one being a pseudogene (16, 17). Nonetheless, only three human CESs are catalytically characterized: CES1, CES2 and CES3 (17).…”

Section: Introductionmentioning

confidence: 99%

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Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs

Xiao

Shi

Yang

et al. 2013

Biochemical Pharmacology

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Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the α/β hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD) and irinotecan. Contrary to the hypothesis, orlistat at 1 nM inhibited CES2 activity by 75% but no inhibition on CES1, placing CES2 one of the most sensitive targets of orlistat. The inhibition varied among some CES2 polymorphic variants. Pretreatment with orlistat reduced the cell killing activity of PPD. Certain mouse but not rat CESs were also highly sensitive. CES2 is responsible for the hydrolysis of many common drugs and abundantly expressed in the gastrointestinal track and liver. Inhibition of this carboxylesterase probably presents a major source for altered therapeutic activity of these medicines if co-administered with orlistat. In addition, orlistat has been linked to various types of organ toxicities, and this study provides an alternative target potentially involved in these toxicological responses.

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