Mammals metabolism, species differences

Oxidation. Although most of the common mammals used as experimental animals carry out oxidation reactions, there may be large variations in the extent to which some of these are carried out. The most common species differences are in the rate at which a particular compound is oxidized rather than the particular pathway through which it is metabolized. Most species are able to hydroxylate aromatic compounds, but there is no apparent species pattern in the ability to carry out this metabolic transformation. 

One of the findings of such studies is that different mammals and even different strains of a given mammal can differ greatly in their metabolism of particular chemicals. This makes extrapolation from studies of mice, particularly of a specific strain of mouse, less certain than was once thought. Also, results from in vitro tests that require metabolic activation may differ among species, tissues, and subcellular fractions. With radiation, one can be reasonably confident of the dose to the germ cells with chemicals, the uncertainties are much greater. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

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). 

This species difference may be associated with the fact that birds and mammals differ profoundly in their nitrogenous metabolism the bird being uricotelic, arid excreting waste protein nitrogen as uric acid, whereas the mammal is ureotelic, and excretes nitrogen chiefly as urea (p. 378). 

The levels of aldehyde oxidase exhibited more pronounced species differences than did those of xanthine oxidase (Figure 2). The levels in the human, dog and cat were low as compared with the other mammals studied, while the levels in the guinea pig and rabbit were very high. These large species variations should be carefully considered in metabolic studies of compounds that are substrates for aldehyde oxidase. 

Exposure to estrogenic compounds through diet will differ for herbivores and carnivores, the latter being most likely to encounter endogenous steroids in their prey. Efficient uptake of steroids in mammals is illustrated by the use of the contraceptive pill, but routes of absorption in invertebrates remain to be determined. The relationship between endocrine disruption and metabolic toxicity, with reduced reproductive viability a secondary consequence of metabolic disturbance, also merits further study in invertebrate species. 

This section demonstrates that (1) free ionic copper (Cu2+) is the most toxic chemical species of copper and that copper bioavailability is modified by many biological and abiotic variables (2) copper metabolism and sensitivity to copper of poikilotherms differs from that of mammals and (3) copper interactions with inorganic and organic chemicals are substantial and must be considered when evaluating copper hazards to natural resources. 

Such observations as these should inject caution into those who speak glibly about what metabolism is like in the mammalian organism. Furthermore, if differences such as these exist among different species of higher mammals, it lends credence to the idea that, within the human species, quantitative differences of a similar nature may exist. Because of differences in enzyme systems and the extent to which different metabolic pathways are utilized in different individuals, it is not at all unreasonable to conclude that different individuals probably have fundamental needs for quite different levels of the thyroid hormone. 

Enzymes of the hepatic microsomes of most marine organisms, with the notable exception of certain molluscs, metabolize xeno-biotic substrates however, as much as 600-fold variations in enzyme activities have been noted between different species of marine teleosts (40). The hepatic enzyme activities of aquatic species are generally lower, with most substrates tested, than the hepatic enzymes of mammals (40). The mixed function oxidase enzymes in marine organisms are inducible by hydrocarbons, such as 3-methylcholanthrene or benzo[a]pyrene. Moreover, it is known... 

Amidases can be found in all kinds of organisms, including insects and plants [24], The distinct activities of these enzymes in different organisms can be exploited for the development of selective insecticides and herbicides that exhibit minimal toxicity for mammals. Thus, the low toxicity in mammals of the malathion derivative dimethoate (4.44) can be attributed to a specific metabolic route that transforms this compound into the nontoxic acid (4.45) [25-27]. However, there are cases in which toxicity is not species-selective. Indeed, in the preparation of these organophosphates, some contaminants that are inhibitors of mammalian carboxylesterase/am-idase may be present [28]. Sometimes the compound itself, and not simply one of its impurities, is toxic. For example, an insecticide such as phos-phamidon (4.46) cannot be detoxified by deamination since it is an amidase inhibitor [24],... 

Feron et al. (1990) concluded that the sensitivity of humans to chemicals is probably not very different from that of other mammals, and that a systematic error is made by carrying out extrapolation by using the body weight approach. For metabolizable compounds, the authors strongly recommended a procedure that takes the metabolic rate into account (1F° ) for scaling across species, i.e., dose correction for differences in body size between experimental animals and humans by the caloric requirement approach (Section 5.3.2.3). This approach was also considered to provide a contribution to reducing the size of the traditional safety factor in a justifiable way. 

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