Esterases species differences

There are marked species differences in A-esterase activity. Birds have very low, often undetectable, levels of activity in plasma toward paraoxon, diazoxon, pirimi-phos-methyl oxon, and chlorpyrifos oxon (Brealey et al. 1980, Mackness et al. 1987, Walker et al. 1991 Figure 2.10). Mammals have much higher plasma A-esterase activities to all of these substrates. The toxicological implications of this are discussed in Chapter 10. Some species of insects have no measurable A-esterase activity, even in strains that have resistance to OPs (Mackness et al. 1982, Walker 1994). These include the peach potato aphid (Myzus persicae Devonshire 1991) and the... 

M., Sugiura, M., Species difference and characterization of intestinal esterase on the hydrolyzing activity of ester-type drugs, Jpn. J. Pharmacol. 

H. Ericsson, B. Tholander, C. G. Regardh, In vitro Hydrolysis Rate and Protein Binding of Clevidipine, a New Ultrashort-Acting Calcium Antagonist Metabolised by Esterases, in Different Animal Species and Man , Eur. J. Pharm. Sci. 1999, 8, 29-37. 

In addition to and like innumerable other examples, these values are taken to reflect to some extent species differences in esterase activity and demonstrate how biological variability can complicate prodrug design. 

Considerable species differences in A-esterase activity exist, ranging from very low or nonexistent in certain birds and fish, to very high in rabbits. Species differences in A-esterase activity could account, at least in part, for species differences in the relative sensitivity to certain phosphorothioate insecticides. For example, birds are much more susceptible to the toxicity of pirimiphos methyl than are mammals. 

Chatthopadhay DP, Dighe SK, Nashikkar AB et al. (1986). Species differences in the in vitro inhibition of grain acetylcholinesterase and carboxyl esterase by mipafox, paraoxon and soman. Pest Biochem Physiol, 26, 202-208. 

Advantage of species differences in metabolism was taken with the synthesis of malathion which is attacked by esterases in mammals and excreted rapidly as the diacid before conversion of the innocuous thio-phosphate to the toxic phosphate. Insects have very low levels of esterases, and metabolism to the lethal oxo metabolite can occur unimpeded (Figure 20). 

The apparent IC50 for test compounds differs between the cell lines, possibly reflecting species differences. However, ratios of ICjo values for NTE AChE show similar patterns >40 for m>n-OPIDN-inducing compounds (paraoxon and malaoxon) and those unlikely to cause OPfDN (chlorpyrifos-oxon, dichlorvos. and trichlorphon) low ratios (some <1) for the other compounds, all of which induce OPIDN. IC50 values for inhibition of esterases are lower than those for cytotoxicity. 

Comparative Toxicokinetics. Syrian hamsters appear to be relatively resistant to the testicular effects of di- -butyl phthalate compared to the rat. A comparative metabolic study with rats and hamsters indicated some quantitative differences between the two species with respect to the excretion of metabolites in the urine. Additional comparative studies, perhaps with other species, may add to our understanding of the mechanisms of toxicity to the male reproductive organs. Since it is well known that there are a wide variety of esterases with varying affinity for different substrates, further information on the substrate specificities of the esterases in various species, and on the enzymes involved in detoxification of di- -butyl phthalate, especially glucuronosyltransferase, could help to understand the biological mechanisms behind the species differences in response to di- -butyl phthalate. 

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. 

Thus a distinction was provided between simple esterases, such as fiver esterase, which catalysed the hydrolysis of simple aliphatic esters but were ineffective towards choline esters. The term 1 cholinesterase was extended to other enzymes, present in blood sera and erythrocytes of other animals, including man, and in nervous tissue, which catalysed the hydrolysis of acetylcholine. It was assumed that only one enzyme was involved until Alles and Hawes2 found that the enzyme present in human erythrocytes readily catalysed the hydrolysis of acetylcholine, but was inactive towards butyrylcholine. Human-serum enzyme, on the other hand, hydrolyses butyrylcholine more rapidly than acetylcholine. The erythrocyte enzyme is sometimes called true cholinesterase, whereas the serum enzyme is sometimes called pseudo-cholinesterase. Stedman,3 however, prefers the names a-cholinesterase for the enzyme more active towards acetylcholine, and / -cholinesterase for the one preferentially hydrolysing butyrylcholine. Enzymes of the first type play a fundamental part in acetylcholine metabolism in vivo. The function of the second type in vivo is obscure. Not everyone agrees with the designation suggested by Stedman. It must also be stressed that enzymes of one type from different species are not always identical in every respect.4 Furthermore,... 

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

Benzyl acetate is quite soluble in lipids and therefore readily absorbed from the gastrointestinal tract and lung, as well as through the skin, in the species investigated. The absorption after oral administration in the rat was delayed if it was administered in com oil or propylene glycol as compared to neat [wet/zy/ene- Cjbenzyl acetate (Chidgey Caldwell, 1986) the peak plasma concentration of benzyl acetate-derived radioactivity occurred later after 1 h versus 4-6 h) and was lower at a 500 mg/kg benzyl acetate dose at 5 mg/kg benzyl acetate, there was no difference. The urinary excretion of the metabolites was also delayed by com oil, but the extent of absorption seemed not to be affected more than 80% was absorbed and excreted within 24 h, mainly in urine and, ultimately, less than 5% in faeces. In plasma and urine, no intact benzyl acetate was detected at any time only its metabolites were present (Chidgey Caldwell, 1986). Benzyl acetate is rapidly hydrolysed by esterases to benzyl alcohol and acetate (Yuan et al., 1995). These esterases are present in plasma and probably also in the tissues it is... 

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. 

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