Carboxylesterase significance

W. Junge, K. Krisch, The Carboxylesterases/Amidases of Mammalian Liver and Their Possible Significance , CRC Crit. Rev. Toxicol. 1975, 3, 371-434. 

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

Capecitabine is a fluoropyrimidine carbamate prodrug with 70-80% oral bioavailability. It undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5 -deoxy-5-fluorocytidine. This is converted to 5 -deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5 -deoxy-5-fluorouridine metabolite is then hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer. 

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2-10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases. 

The in vivo metabolism of capecitabine (1) to the active tumor cytotoxic substance 5-fluorouracil (5) is now fairly well understood. When capecitabine is administered orally it is delivered to the small intestine, where it is not a substrate for thymidine phosphorylase in intestinal tissue, and so passes through the intestinal mucosa as an intact molecule and into the bloodstream. When 1 reaches the liver, the carbamate moiety is hydrolyzed through the action of carboxylesterase enzymes, liberating 5 -deoxy-5-fluorocytidine (5 -DFCR, 10). DFUR is partially stable in systemic circulation, but eventually diffuses into tumor cell tissue where it is transformed into 5 -deoxy-5-fluorouridine (5 -DFUR, 9) by cytidine deaminase, an enzyme present in high concentrations in various types of human cancers compared to adjacent healthy cells (although it is present in significantly lower levels in the liver). Within the tumor, 5-... 

There are two types of esterases that are important in metabolizing insecticides, namely, carboxylesterases and phosphatases (also called phosphorotriester hydrolases or phosphotriesterases). Carboxylesterases, which are B-esterases, play significant roles in degrading organophosphates, carbamates, pyrethroids, and some juvenoids in insects. The best example is malathion hydrolysis, which yields both a- and (i-monoacids and ethanol (Figure 8.10). 

Both Aphis gossypii and Myras persicae are major agricultural pests, and insecticide resistance in these species is a significant problem. Organophosphate and carbamate tolerance in these aphids has been related to detoxification via increased carboxylesterase activity Suzuki el al., 1993 Devonshire and Moores, 1977). 

Cocaine metabolism and disposition following acute ethanol administration were studied in the rat to determine if the in vitro effects of ethanol on cocaine methyl esterase and ethyl transferase activities had significance in vivo (Zachman et al. 1993). The rat was used as it possesses both ethyl transferase and methyl esterase activities, is frequently employed for behavioral and toxicity studies of cocaine, and the size provides sufficient tissue for anal 4 ical work. This study was designed to address three questions. First, do significant concentrations of cocaethylene form and accumulate in tissues with controlled coadministrations of cocaine and alcohol Second, does ethanol administration significantly diminish the hydrolysis of cocaine to benzoylecgonine and methanol, as occurs in vitro when cocaine and ethanol are coincubated with purified human liver carboxylesterase (Brzezinski et al. 1994 Dean et al. 1991) Third, does ethanol inhibition of cocaine methyl ester hydrolysis increase the N-oxidative metabolism of cocaine, as noted when rodents are pretreated with nonspecific esterase inhibitors (Thompson etal. 1979) ... 

In case of CarE there was lack of significant differences between the mean activity in the midgut of males from both sites. Reversibly, females from both sites showed a stimulation of CarE activity in this organ (Fig. 8). Ovaries of females from Szopienice had carboxylesterases unaffected by cadmium, with higher activity level than ovaries of females from Tychy. Induction of this enzyme by cadmium was observed in testes, with more pronounced effects in males from Szopienice (Fig. 8). 

In studies in human liver microsomes, nifedipine, clonazepam, methylprednisolone, omeprazole, and vinorelbine had significant effects on the metabolism of irinotecan. However, only the effect of vinorelbine occurred at a concentration considered clinically relevant. Similarly, of various potential carboxylesterase inhibitors, only physostigmine was considered sufficiently potent to possibly inhibit irinotecan activation. Further study is needed to assess the clinical relevance of these findings. 

In an another application, the enantioselectivity of carboxylesterase A (CesA) from Bacillus subtilis towards butyrate and caprilate esters of 1,2-O-isopropylideneglycerol was improved up to 13-fold by structure-guided mutagenesis. The mutagenesis of positions 166 and 182 in CesA yielded novel variants with enhanced enantioselectivity without significant loss of catalytic activity. ... 

The chiral stractures (stereochemistry) are not shown in Table Dll. The trans-isomers are more readily hydrolyzed than are the c/s-isomers by carboxylesterases and are perhaps more readily hydroxylated by P450 isozymes. Kaneko et al. (1984) studied the metabolism of six isomer preparations [(IR-trans), (IRS-trans), (1 S-trans), (IR-cis), (IRS-cis), and (IS-cis)] of phenothrin after single oral administration of each " C-labeled isomer or isomer mixture at 10 mg kg to rats and mice. There was no significant difference between the elimination of the (IR-tram) and (IRS-trons) or the (lR-c ) and (IRS-c/s) isomers. However, the (lS-/rans) and (IS-c/s) isomers were eliminated to a greater extent in urine than were the (1R-) and (1RS-) trans- and cis-isomers, respectively (Izumi et al. 1984). 

The results suggested that a significant portion of the microsomal activity was catalyzed by hCE-2. An antibody was not available for detecting or measuring hCE-2. Turnover numbers ( cat/ m> mM min ) indicate that trani-permethrin is as efficiently hydrolyzed by hCE-1 as it is for hCE-2. Bioresmethrin is not hydrolyzed by hCE-2 suggesting that metabolism is primarily mediated by hCE-1. The rates of hydrolytic metabolism by rabbit carboxylesterase followed the order bioresmethrin > frans-permethrin > cA-permethrin > deltamethrin > alpha-cypermethrin. Ross et al. (2006) did not extrapolate hydrolytic in vitro V ,ax values (nmol min mg ofmicrosomalprotein)intoin vivo values (p,mol h kg of body weight (bwt)) for use in PBPK models. 

This information was used to cmistruct a PBPK/PD model in the adult male rat (MirfazaeUan et al. 2006). Godin et al. (2006) examined species differences between rat and human liver microsomal carboxylesterases. A significant species difference was noted in the in vitro biotransformation of deltamethrin, due in part to differences in the rate of hydrolysis by human liver microsomes. Godin et al. (2007) identified the rat and human CYP450 isoforms, and rat serum esterases that metabolize deltamethrin and esfenvalerate. Differences in the rates of hepatic oxidative metabolism were related to expression levels (abundance) of the individual P450 isoforms rather than their specific activity. 

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