Xenobiotics carboxylesterases

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

Ross MK, Crow JA (2007) Human carboxylesterases and their role in xenobiotic and endobi-otic metabolism. J Biochem Mol Toxicol 21 187-196... 

T. Satoh, Role of Carboxylesterases in Xenobiotic Metabolism , in Reviews in Biochemical Toxicology , Eds. E. Hodgson, J. R. Bend, R. M. Philpot, Elsevier, New York,... 

Enol esters are distinct from other esters not because of a particular stability or lability toward hydrolases, but due to their hydrolysis releasing a ghost alcohol (an enol), which may immediately tautomerize to the corresponding aldehyde or ketone. A well-studied example is that of vinyl acetate (CH3-C0-0-CH=CH2), a xenobiotic of great industrial importance that, upon hydrolysis, liberates acetic acid (CH3-CO-OH) and acetaldehyde (CH3-CHO), the stable tautomer of vinyl alcohol [25], The results of two studies are compiled in Table 7.1, and demonstrate that vinyl acetate is a very good substrate of carboxylesterase (EC 3.1.1.1) but not of acetylcholinesterase (EC 3.1.1.7) or cholinesterase (EC 3.1.1.8). The presence of carboxylesterase in rat plasma but not in human plasma explains the difference between these two preparations, although the different experimental conditions in the two studies make further interpretation difficult. 

It, thus, appears that the capacity to catalyze reactions of transesterification and esterification is a characteristic of various hydrolases (Chapt. 3). Apart from the carboxylesterases discussed here, lipoprotein lipase has the capacity to synthesize fatty acid ethyl esters from ethanol and triglycerides, or even fatty acids [127]. Ethanol, 2-chloroethanol, and other primary alcohols serve to esterify endogenous fatty acids and a number of xenobiotic acids [128-130]. In this context, it is interesting to note that the same human liver carboxylesterase was able to catalyze the hydrolysis of cocaine to benzoylecgonine, the transesterification of cocaine, and the ethyl esterification of fatty acids [131]. 

The hydrolysis of esters by esterases and of amides by amidases constitutes one of the most common enzymatic reactions of xenobiotics in humans and other animal species. Because both the number of enzymes involved in hydrolytic attack and the number of substrates for them is large, it is not surprising to observe interspecific differences in the disposition of xenobiotics due to variations in these enzymes. In mammals the presence of carboxylesterase that hydrolyzes malathion but is generally absent in insects explains the remarkable selectivity of this insecticide. As with esters, wide differences exist between species in the rates of hydrolysis of various amides in vivo. Fluoracetamide is less toxic to mice than to the American cockroach. This is explained by the faster release of the toxic fluoroacetate in insects as compared with mice. The insecticide dimethoate is susceptible to the attack of both esterases and amidases, yielding nontoxic products. In the rat and mouse, both reactions occur, whereas sheep liver contains only the amidases and that of guinea pig only the esterase. The relative rates of these degradative enzymes in insects are very low as compared with those of mammals, however, and this correlates well with the high selectivity of dimethoate. 

The inhibition of the carboxylesterase that hydrolyzes malathion by organophospho-rus compounds, such as EPN is a further example of xenobiotic interaction resulting from irreversible inhibition. In this case the enzyme is phosphorylated by the inhibitor. 

The inhibition by other organophosphate compounds of the carboxylesterase which hydrolyzes malathion is a further example of xenobiotic interaction resulting from irreversible inhibition because, in this case, the enzyme is phosphorylated by the inhibitor. A second type of inhibition involving organophosphorus insecticides involves those containing the P=S moiety. During CYP activation to the esterase-inhibiting oxon, reactive sulfur is released that inhibits CYP isoforms by an irreversible interaction with the heme iron. As a result, these chemicals are inhibitors of the metabolism of other xenobiotics, such as carbaryl and fipronil, and are potent inhibitors of the metabolism of steroid hormones such as testosterone and estradiol. 

NousianinenU (1984) Inducibility of Carboxylesterases by Xenobiotics in the Rat, pp. 1-55. Dissertation, submitted to the University of Kuopio. 

The induction of carboxylesterase activity has also been observed in animals exposed to PAHs (Nousiainen et al. 1984). Benzo[a]pyrene, benz[a]anthracene, and chrysene were moderate inducers of hepatic carboxylesterase activity in rats that were intragastrically administered 50,100, and 150 mg/kg/day (100 mg/kg/day for chrysene), respectively, for 4 days. However, rats administered 100 mg/kg/day anthracene or phenanthrene did not exhibit induction of hepatic carboxylesterase activity. Induction of hepatic microsomal enzymes generally results in enhanced biotransformation of other xenobiotics (to either more or less toxic forms). 

Plasma esterases such as cholinesterase and arylesterases are involved in the hydrolysis of some xenobiotics and may affect the elimination of some compounds. Carboxylesterases appear to be absent from some laboratory animals, but are present in rats and guinea pigs and may also play a part in the hydrolysis of xenobiotics (Williams 1987). 

A considerable number of enzymes belong to a group called carboxylesterases (CBEs). Together, they are able to hydrolyze a wide range of endogenous and xenobiotic esters. Typical experimental substrates are... 

Hosokawa, M., Watanabe, N., Tsukada, E., Fukumoto, M., Chiba, K., Takeya, M., Imai, T., Sasaki, Y.F. Sato, T. (2001) Multiplicity of carboxylesterase isozymes in mammals and humans role in metabolic activation of prodrugs. Yakubutsu Dotai (Xenobiotic Metabolism and Disposition), 16(suppl.), 92-93. 

Interestingly, imidazoles were found as the inhibitors of carboxylesterases, which could relate in the metabolism of esterified drugs and xenobiotics [45],... 

Cummins, I. Landrum, M. Steel, P. G. Edwards, R. Structure activity studies with xenobiotic substrates using carboxylesterases isolated from Arabidopsis thaliana. Phytochemistry 2007,68, 811-818. 

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