Marked species

Moreover, receptors also control gastric acid release, although some marked species dependence is noticed (8). However, appHcation of agonists in this area does not seem to be probable the antagonists and the proton pump inhibitors serve quite weU. 

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... 

Another interesting finding was that two structurally close analogues of (15a), namely compounds (15b) and (15c), showed marked species-related differences in activity they behaved as weak antagonists towards hTRPVl, and weak agonists towards rTRPVl [78]. This observation indicates that great caution should be taken when extrapolating TRPVl actions from animal models to humans ... 

There are marked species differences in susceptibility to specific emetogens. For example, dog and man are very sensitive to apomorphine [40], while the rhesus monkey is completely resistant [41]. The ferret exhibits intermediate sensitivity to apomorphine, but there may be some controversy regarding this species [42-44], On the other hand, the ferret shows high sensitivity to radiation-induced emesis [44] followed by dog, man, monkey and cat. The cat in general is more resistant to apomorphine and radiation-induced emesis than dog or man [40, 45],... 

Marked species differences in hydrolytic cleavage were also observed for pranlukast (4.160), a leukotriene receptor antagonist. In rats, amide hydrolysis represented a major metabolic pathway, whereas, in humans, it was apparently absent. Investigations with purified enzymes showed that pranlukast... 

Interestingly, there is a marked species difference in the in vitro hydrolysis of carbamazepine 10,11-epoxide, such that the reaction was observed only in liver microsomes from humans but not in liver microsomal or cytosolic preparations from dogs, rabbits, hamsters, rats, or mice [181][196], Thus, carbamazepine appears to be a very poor substrate for EH, in analogy with the simpler analogues 10.129 (X = RN, RCH, or RCH=C). The human enzyme is exceptional in this respect, but not, however, in the steric course of the reaction. The diol formed (10.131, X = H2NCON) is mostly the trans-(10.S, 11. S )-enaniiomer [196], In other words, the product enantioselectivity of the hydration of carbamazepine epoxide catalyzed by human EH is the same as that of di benzol a,oxide catalyzed by rabbit microsomal EH, discussed above. 

Interpretation of results for the A -methylated aralkylguanidines (Table 3.29) is less clear, as there appear to be marked species differences. Monoamine oxidase in rat tissues 387] is more sensitive to inhibition by compounds of this type than that in cat or guinea-pig tissues [389], and the increase in potency found on -chloro substitution is less marked in other species than it is in rats. For any single aryl group A -methylation or A A"-dimethylation may either slightly increase or decrease activity. 

MOCA causes low to moderate acute toxicity in animals, with marked species... 

Recent evidence confirms that species differences can involve more than one aspect of PPARa-mediated regulation of gene expression. The insensitivity of human liver to rodent peroxisome proliferators is associated with low levels of expression of PPARa in human liver. Marked species differences in the expression of PPARa mRNA have been demonstrated between rodent and human liver, with the latter expressing 1-10% of the levels found in mouse or rat liver (Palmer et al, 1994 Tugwood et al, 1996 Palmer etal, 1998). Using a sensitive and specific immuno/DNA binding assay. Palmer et al (1998) have shown that active PPARa protein is expressed at variable concentrations in human livers. The study compared 20 different human livers and found that those with the highest levels of PPARa protein expression contained less than 10% of the level in mice. Most of the samples (13/20) contained no detectable PPARa activity, but did... 

Marked species differences in hepatic peroxisome proliferation have been reported (Ashby et al, 1994 lARC, 1995 Lake, 1995a,b Cattley et al, 1998). No study has yet compared the responsiveness of human versus rodent livers in vivo or hepatocytes in vitro to cinnamyl anthranilate however, a growing body of evidence concerning the molecular basis of peroxisome proliferation indicates that human livers and hepatocytes would be refractory to induction of peroxisome proliferation by cinnamyl anthranilate (Doull et al., 1999). 

Histamine was synthesized in 1907 and later isolated from mammalian tissues. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between the effects of intravenously administered histamine and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic (such as urticaria) and inflammatory reactions, although it plays only a modest role in anaphylaxis. Histamine plays an important role in gastric acid secretion (see Chapter 62) and functions as a neurotransmitter and neuromodulator (see Chapters 6 and 21). Newer evidence indicates that histamine also plays a role in chemotaxis of white blood cells. 

However, there are known instances of differences in the preferred route of metabolism, which are important in toxicity, as well as simple differences in the route of a particular oxidation. For example, the oxidative metabolism of ethylene glycol gives rise to either carbon dioxide or oxalic acid (Fig. 5.7). The relative importance of these two pathways is reflected in the toxicity. Thus, the production of oxalic acid is in the order cat>rat> rabbit, and this is also the order of increasing toxicity (Fig. 5.8). The aromatic hydroxylation of aniline (Fig. 5.9) shows marked species differences in the position of substitution, as shown in Table 5.9. Thus carnivores such as the ferret, cat, and dog excrete mainly o-aminophenol, whereas herbivores such as the rabbit and guinea pig excrete mainly p-aminophenol. The rat, an omnivore, is intermediate. 

Another example is the metabolism of amphetamine, which reveals marked species differences in the preferred route, as shown in Figure 5.10. 

Marked species differences have been reported for the metabolic activation of acrylonitrile to CEO in vitro. The and for microsomes from mouse liver and... 

For CP-96,345 and RP-67580, and also other NK1 antagonists, marked species variants were observed in pharmacological studies. RP-67580 has a higher affinity for the rat and mouse NK1 receptors, whereas CP-96,345 preferentially binds to human and guinea pig NK1 receptors. CP-96,345 has a 90-fold selectivity for the human NK1 receptor over the rat NK1 receptor, while the agonist SP shows no such selectivity (Sachais et al., 1993). 

Since histamine H3-receptors on the heart are characterised by marked species differences, the effects mediated by these receptors will be considered in relation to the different animal models where these receptors have been investigated. 

A marked difference in hepatic activity of aldehyde oxidase between rats and monkeys was found to be responsible for the reported marked species difference in the metabolism of Zaleplon in vivo. In the postmito-chondrial fractions, S-9s, from liver homogenates of these animals, zaleplon was transformed in the presence of NADPH into the side chain oxidation product, N-desethyl-zaleplon, and the aromatic ring oxidation product, 5-oxo-zaleplon. In the rat S-9, N-desethyl-zaleplon and 5-oxo-zaleplon were a major and a very minor metabolites, respectively. 

Histamine was synthesized in 1907 and later isolated from mammalian tissues. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between histamine s actions and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic and... 

Karim et al determined that the main pathway of disopyramide metabolism involved N-dealky-lation of the isopropyl group and arylhydroxy-lation, with a marked species difference in biotransformation between dog, rat, and man. 

Presynaptic neuropeptide Y receptors have been identified in the sympathetic, parasympathetic and enteric nervous system, on sensory neurones, and on many sites in the CNS they inhibit the release of 11 different transmitters (Table 3). Most presynaptic neuropeptide Y receptors are heteroreceptors, but some serve as autoreceptors, both in the sympathetic nervous system (pig spleen and kidney) and the brain (rat hypothalamus) (Table 3). Marked species differences occur. For example, Y2 receptors inhibit the sympathetically mediated tachycardia, the vagally mediated bradycardia, and the vagally mediated bronchoconstriction in the guinea pig but not in the rabbit (Serone et al. 1999 Abrahamsson 2000). Moreover, Y2 receptors inhibit noradrenaline release in the guinea pig carotid but not femoral artery, and conversely inhibit noradrenaline release in the rat femoral but not carotid artery (Potter and Tripovic 2006). 

Kawashima K, Hosoi K, Naruke T, et al. Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats. Drug Metab Dispos 1999 27 422-428. 

Studies on the physiological effect of LTP-I have been assisted by the recognition that there are marked species differences in activity. Rabbit plasma contains between two and three times the activity in human plasma, and plasma from rats, sheep, and pigs, for instance, contains less than 20% of the activity of human plasma (HI). Whereas rat plasma is deficient in cholesteryl ester and triglyceride transfer activity, facilitated phospholipid transfer activity is not impaired (II, 12, T4). The reason is unknown it is possible that rat plasma contains a different lipid transfer protein (T2), perhaps homologous to the LTP-2 reported in human plasma (A17). 

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