Target Organ Toxicity in Marine and Freshwater Teleosts. Vol. 2

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., 1994; Eliasson and Kenna, 1996).BothCYP2E and CYP1A are known to exist in fish.Furthermore, the lymphoid tissues of thegut are exposed to dietary toxicants before passing into the portal system en route to the120 FISH IMMUNOTOXICOLOGYliver for transformation.As the gut of fish is an active participant in xenobiotic metabolism(Van Veld et al., 1987), gut-associated lymphoid tissues (GALT) and mucosal lymphoidtissues (MALT) are expected to lead to the generation of active metabolites not only ofprocarcinogens, promutagens, and proimmunotoxicants, but of prohaptens as well.As mentioned earlier, the integument is the most important immune organ and this isclearly seen in the case of contact hypersensitivity.Skin immunity of higher vertebrates isregulated primarily through the interactions of Langerhans cells and T cells, and, in comecases, macrophages.Langerhans cells are a good source of CYP1A enzymes and are able tometabolize dimethylbenz-(a)-anthracene to haptens.A similar role for fish integument hasnot been established, but is highly likely.The importance of phagocytes to both innate and specific immune responses is wellknown, however their role(s) in generating haptens should be of great interests to fishimmunotoxicologists.In what is considered to be a classic study, Ladies et al.(1992)demonstrated that mouse splenic macrophages metabolize benzo(a)pyrene to a mutagenand carcinogenic diol-epoxide structures similar to those formed by hepatic parenchymalcells.Rose et al.(2000) demonstrated the same for mummichog, Fundulus heteroclitus,anterior kidney cells.Furthermore, these metabolites from mummichog were able toform DNA adducts; a possible first step in generating auto-DNA antibodies.However,cells other than macrophages, including lymphocytes, eosinophilic granular cells,endothelial cells, and inter-renal cells, are present in these preparations.Pure populationsof macrophages will be needed to equate these findings with those of Ladies et al.(1992),but the likelihood of similar responses is good.Regardless of phylogeny, the ability of neutrophils, macrophages, or eosinophils togenerate reactive electrophiles from procarcinogens and prohaptens implies the presenceof CYP-like enzymes.These cell types are an abundant source of myeloperoxidase,prostaglandin H synthase, and some cytochrome P450 enzymes.The first two have broadsubstrate specificity, especially prostaglandin H synthase, a enzyme with co-oxidation-peroxidation as its primary function.It is this enzyme system that Ladies et al.(1992) mayhave been describing during the metabolism of benzo(a)pyrene to reactive intermediatesby leukocytes.At least in higher vertebrates, prostaglandin H synthase is inducible byproinflammatory signals and is called cyclooxygenase 2 (COX-2).If and when thepresence and function of COX-2 is established in fish, phagocytes will be credited withhaving a key role in metabolizing certain xenobiotics not only to carcinogenicintermediates but perhaps to haptens as well.Once the preimmunologic stage has been set by the generation of hapten-self proteincarriers, T cells need to be sensitized.In the classic sense, this is carried out via thepresentation of hapten to T cells in the context of MHC-II/TCR interactions.Cognate orcell-to-cell contact and generation of primarily two co-stimulatory signals is required.Signal 1 is delivered by the interaction of MCH-II/hapten interaction with the TCR andCD3 components.Signal 2 is a generic term referring to a variety of ligand-initiated signaltransduction events between T and antigen-presenting cells and adhesion molecules thatcontribute to T-cell activation and subsequent events (Table 3.2).As described earlier,fish do have T and B lymphocytes as well as the ability to process and present antigens to Tcells (Clem et al., 1996).The ability of fish to generate self protein carrier-hapten systemsFigure 3.7 Haptens comprise organic compounds and metal ions, and bind to proteins forming either covalent bonds (a) or co-ordinated complexes (b).Organic haptens forming covalent bonds bind to a single amino acid side-chain; the covalent binding of trinitrophenyl (TNP) to lysine is shown.Metalcomplexes consist of a central metal ion and a set of atoms, ions or small molecules, regarded as ligands [ Pobierz całość w formacie PDF ]

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