Altered Xenobiotic Transport

Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 2002 12 395-405. 

Cooper, P.S., W.K. Vogelbein and P.A. Van Veld. Altered expression of the xenobiotic transporter P-glycoprotein in liver and liver tumours of the mummichog (Fundulus heteroclitus) from a creosote-contaminated environment. Biomarkers 4 48-58, 1999. 

Our questions broadened to consider how the transport and metabolic capabilities of these aquatic species compare with those of mammalian species. One reason for asking such a question is to assess whether the presence or absence of these capabilities alters the ability of fish to survive in toxic environments. Survival mechanisms fall into two catagories - behavioral and physiologic. An example of a behavioral mechanism could be as simple as a fish avoiding that area of a stream which contains toxic quantitites of phenol. When external perturbations caused by pollutants are small, homeostatic mechanisms such as those of the liver and kidney, allow fish to adapt to the body of water in which they exist. The problem then is related to defining the limits to which homeostatic phenomena can be stressed in aquatic species. An important reason to establish such information in fish is that bodies of water are the "ultimate sink" for a number of pollutants (12). Thus, while a behavioral response such as removing itself from a toxic environment is invariably available to a mammalian species, this type of response is impossible for a fish if a toxic xenobiotic occurs uniformly throughout an entire body of water. 

The kidneys are susceptible to toxicity from xenobiotics (Fig. 7.1) because they too have a high blood flow. Cells of the tubular nephron face double-sided exposure, to agents in the blood on the basolateral side and in the Altered urine on the luminal side. Proximal tubule cells are generally the site of nephrotoxicity, since these cells have an abundance of cytochrome P450 and can transport organic anions and cations from the blood into the cells, thereby concentrating these chemicals manyfold. 

The majority of xenobiotics that enter the body tissues are lipophilic, a property that enables them to penetrate lipid membranes and to be transported by lipoproteins in body fluids. The metabolism of xenobiotics, carried out by a number of relatively nonspecific enzymes, usually consists of two phases. During phase I, a polar group is introduced into the molecule and although this increases the molecule s water solubility, the most important effect is to render the xenobiotic a suitable substrate for phase II reactions. In phase II reactions, the altered compounds combine with an endogenous substrate to produce a water-soluble conjugation product that is readily excreted. Although this sequence of events is generally a detoxication mechanism, in some cases the intermediates or final products are more toxic than the parent compound, and the sequence is termed an activation or intoxication mechanism. See Chapter 20 for discussion of activation and toxicity. 

Kidneys have relatively low xenobiotic-metabolizing enzyme activities, and chemically induced nephrotoxicity has been assumed to be produced by toxic intermediates generated in the liver and transported to the kidney. If a single hepatic metabolite of chloroform produced both kidney and liver injury, species, strain, and sex differences in susceptibility to chloroform nephro- and hepatotoxicity should be similar. However, species, strain and sex differences in susceptibility to chloroform nephrotoxicity are not consistent with those of chloroform hepatotoxicity. In addition, several modulators of tissue xenobiotic-metabolizing activities alter... 

Endocrine disruption which is independent of interactions between xenobiotics and endogenous hormone receptors can occur in a variety of different ways, including alterations in the number of hormone receptor sites (up- or down-regulation) or direct or indirect hormone modifications which alter hormonal function (Evans, 2007 Keith, 1997). Xenobiotics can change the rate of synthesis or destruction of endogenous hormones and can alter how hormones are stored, how they are released into and/or transported within the circulation, or even how they are eventually cleared from the body (Capen, 2008 Evans, 2007 Keith, 1997 Sikka et al, 2005). Any xenobiotic toxic to hormone-producing organs or tissues (e.g. testis and ovary) also has the potential to decrease hormone synthesis and thereby indirectly cause endocrine disruption (Devine and Hoyer, 2005 Evans, 2007). 

Proximal tubular injury due to nephrotoxicants occurs more frequently than other nephrotoxic effects, and this probably reflects a combination of the proportion of the total renal blood supply received by the renal cortex and the number of xenobiotics reabsorbed and excreted within the proximal tubule. Xenobiotics can alter or inhibit the transport processes of passive diffusion and/or carrier transporters for both anionic/base and cationic molecules. 

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