Mammalian responses

Fig. 9.3. Immunoglobulin E (IgE) and mast cell activation are important components of the mammalian response to cestode infections (ADCC, antibody dependent cell-mediated cytotoxicity Ag, antigen EO, eosinophils Feel, high affinity receptor for Fc portion of IgE LTs, leukotrienes Mac, macrophages NO, nitric oxide PGs, prostaglandins TNFa, tumour necrosis factor alpha).

These definitions have been modified by several authors (Beauchamp, Doty, Moulton, Mugford, 1976, 1979 Katz Shorey, 1979), who have pointed out that mammalian responses may depend upon intricate combinations of chemical and non-chemical cues as well as a mammal s physiological state and past experience (all of which have been found to modify responses to pheromones in insects as well). To complicate matters further, humans also have cultural factors to incorporate into an already complex situation. 

Sung, J.H. et al., 2014. Using physiologically-based pharmacoki-netic-guided body-on-a-chip systems to predict mammalian response to drug and chemical exposure. Experimental Biology and Medicine (Maywood, N.J.), 239, pp. 1225-1239. 

Although in vitro mutagenicity tests suggest that some nitrofurans in general provoke a positive response, use of in vivo mammalian systems has produced equivocal or negative results. 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

Animal and Human Toxicity. The acute toxicity of lindane depends on the age, sex, and animal species, and on the route of adrninistration. The oral LD q in mice, rats, and guinea pigs is 86, 125—230, and 100—127 mg/kg, respectively. In contrast, most of the other isomers were considerably more toxic (94,95). Some of the other toxic responses caused by lindane in laboratory animals include hepato- and nephotoxicity, reproductive and embryotoxicity, mutagenicity in some short-term in vitro bioassays, and carcinogenicity (80). The mechanism of the lindane-induced response is not known. Only minimal data are available on the mammalian toxicides of hexachlorocyclopentadiene. 

The mammalian and avian immune systems function similarly both incorporate humoral and cell-mediated cytotoxic mechanisms, " and are thought to share a 160m year old relationship with the reptilian immune system. The immune system of mammals shows sexual dimorphism " a greater immune response is normally observed in females, which has been attributed to differences in steroid hormone concentration. In the toad Bufo regularis, sexual dimorphism of the immune system is also apparent. ... 

It appears that chromium(III) is an essential trace element in mammalian metabolism and, together with insulin, is responsible for the clearance of glucose from the blood-stream. Tungsten too has been found to have a role in some enzymes converting CO2 into formic acid but, from the point of view of biological activity, the focus of interest in this group is unquestionably on molybdenum. 

By the turn of the century the theory of chemical mediation of physiologic responses had gained some currency. There ensued in some laboratories an intense search for endogenous chemical modifiers of bodily responses. The first such agent to be isolated from mammalian tissue was the ubiquitous hormone, epinephrine—at that time known as adrenaline. This compound has played an important role in pharmacology as well as in medicinal chemistry. 

Another major second messenger in cells is calcium ion. Virtually any mammalian cell line can be used to measure transient calcium currents in fluorescence assays when cells are preloaded with an indicator dye that allows monitoring of changes in cytosolic calcium concentration. These responses can be observed in real time, but a characteristic of these responses is that they are transient. This may lead to problems with hemi-equilibria in antagonist studies whereby the maximal responses to agonists may be depressed in the presence of antagonists. These effects are discussed more fully in Chapter 6. 

Other examples of a-keto acid-dependent enzymes are mammalian proline hydroxylase and bacterial clavaminate synthase [113]. The latter enzyme is of particular interest as it is responsible for the catalysis of three individual steps in the biosynthesis of the (3-lactamase inhibitor clavulanic acid (Scheme 10.30). 

All mammalian cells are virtually capable of producing CO with heme as the main substrate (Fig. 1) [5]. Enzymatic heme metabolism in vivo is mainly catalyzed by heme oxygenase (HO). In the presence of HO, the porphyrin ring of heme is broken and oxidized at the a-methene bridge, producing equimolar amounts of CO, ferrous iron, and biliverdin. Three isoforms of HO have been identified. Inducible HO-1 (32 kDa) is mostly recognized for its upregulation in response... 

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