Metabolism species’ differences

In general, it is easier to use models such as these to predict the distribution of chemicals (i.e., relationship between exposure and tissue concentration) than it is to predict their toxic action. The relationship between tissue concentration and toxicity is not straightforward for a diverse group of compounds, and depends on their mode of action. Even with distribution models, however, the picture can be complicated by species differences in metabolism, as in the case of models for bioconcentration and bioaccumulation (see Chapter 4). Rapid metabolism can lead to lower tissue concentrations than would be predicted from a simple model based on values. Thus, such models need to be used with caution when dealing with different species. 

Batten, P.L. and Hutson, D.H. (1995). Species differences and other factors affecting metaholism and extrapolation to man. In The Metabolism of Agrochemicals, Vol. 8 of Progress in Pesticide Biochemistry and Toxicology. D.H. Hutson and G.D. Paulson (Eds.). Chichester, UK John Wiley, 267-308. 

Walker, C.H. (1978). Species differences in microsomal monooxygenase activities and their relationship to biological half lives. Drug Metabolism Reviews 7(2), 295-323. 

Larson JL, Bull RJ. 1992b. Species differences in the metabolism of trichloroethylene to the carcinogenic metabolites trichloroacetate and dichloroacetate. Toxicol Appl Pharmacol 115 278-285. 

When applying any of these models it is crucial to understand the main transport mechanisms as well as the metabolic route and characterization of the activity of the transporter/enzyme involved. It is well recognized that the activities of carrier-mediated processes in Caco-2 cells are considerably lower than in vivo [20, 42, 48] therefore, it is crucial to extrapolate in vitro cell culture data to the in vivo situation with great care [18, 20, 42, 48], This is especially important when carrier-mediated processes are involved, as evidenced by a recent report which showed significant differences in gene expression levels for transporters, channels and metabolizing enzymes in Caco-2 cells than in human duodenum [48], If an animal model is used, then potential species differences must also be considered [18, 20, 45],... 

Lin G, Cui Y-Y, Liu X-Q and Wang Z-T (2002b), Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloids clivorine , Chem Res Toxicol, 15, 1421-1428. 

Urinary excretion patterns of thiocyanate suggest that there are quantitative species differences in acrylonitrile metabolism (Ahmed and Patel 1981). Thiocyanate was identified as a metabolite in rats, mice, rabbits and Chinese hamsters. About 20 to 23% of the administered dose was excreted as thiocyanate in rats, rabbits and Chinese hamsters, while 35% was excreted as thiocyanate in mice (Gut et al. 1975). It has also been observed that mice metabolize acrylonitrile more rapidly than rats (Ahmed and Patel 1981 Gut et al. 1975). Maximum blood cyanide concentrations were observed 1 hour after dosing in mice, but 3 hours after dosing in rats (Ahmed and Patel 1981). In mice, thiocyanate was present in the urine within 4 hours of dosing, while in rats, thiocyanate was present in urine only at time intervals longer than 4 hours (Gut et al. 1975). 

Developmental Toxicity. No information is available on developmental effects of acrylonitrile in humans by any route of exposure. Acrylonitrile is teratogenic and embryotoxic in rats both by the oral and inhalation routes of exposure. Developmental studies on other animal species have not been conducted. Because species differences for acute acrylonitrile toxicity and metabolism have been demonstrated, additional developmental studies in other species using various dose levels would be valuable in evaluating the potential for acrylonitrile to cause developmental effects in humans. Because the available oral study was conducted by gavage, additional studies are needed to determine if these effects will occur following ingestion of drinking water or food. 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of acrylonitrile in rats has been studied. Limited work in other species suggests that important species differences do exist. Further evaluation of these differences, and comparison of metabolic patterns in humans with those of animals would assist in determining the most appropriate animal species for evaluating the hazard and risk of human exposure to acrylonitrile. 

The proposed fenvalerate metabolic pathways in dogs (Kaneko et al. 1984) suggest that species differences and pathways are important and require more research. 

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

NADPH-independent hydrolytic metabolism. The CLint for deltamethrin was estimated to be twice as rapid in humans as in rats on a per kg body weight basis. Metabolism by purified rat and human CESs was used to examine further the species differences in hydrolysis of deltamethrin and esfenvalerate. Results of CES metabolism revealed that hCEl was markedly more active toward deltamethrin than the Class I rat CESs, hydrolase A and B, and the Class II human CES, hCE2 however, hydrolase A metabolized esfenvalerate twice as fast as hCEl, whereas hydrolase B and hCEl hydrolyzed esfenvalerate at equal rates. These studies demonstrated a significant species difference in the in vitro pathways of biotransformation of deltamethrin in rat and human liver microsomes, which was due in part to differences in the intrinsic activities of rat and human CESs. 

Huckle KR, Hutson DH, Millbum P (1981) Species differences in the metabolism of 3-phenoxybenzoic acid. Dmg Metab Dispos 9 352-359... 

Godin SJ, Scollon EJ, Hughes MF, Potter PM, DeVito MJ, Ross MK (2006) Species differences in the in vitro metabolism of deltamethrin and esfenvalerate differential oxidative and hydrolytic metabolism by humans and rats. Drug Metab Dispos 34 1764-1771... 

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