Xenobiotics tissue distribution

Zhang H, LeCluyse E, LiuL, et al. Rat pregnane X receptor Molecular cloning, tissue distribution, and xenobiotic regulation. Arch Biochem Biophys 1999 368 14-22. 

Immunohistochemical studies on tissue distribution of P-gp Immunohistochemical studies on tissue-specific distribution of P-gp in fish revealed a pattern similar to that described in mammals, i.e. immunoreactive P-gp occurs in epithelial tissues involved in secretion, absorption or serving a barrier function. Further, P-gp-like proteins were observed at the bile canaliculi of the liver, in the proximal tubules of the excretory kidney, at the endothelia of brain capillaries, in the intestinal tract, exocrine pancreas, operculi, gills, pseudobranch, gas gland, interrenal tissue and skeletal muscle (Table 5). This tissue distribution is in agreement with the assumed role of P-gp in protection against xenobiotics. 

Tissue Distribution Though they are most densely distributed in the liver and the intestines, GYP enzymes that are responsible for xenobiotic metabolism are also found in the placenta, lung, lymphocytes, macrophages, kidney, and even the brain. Most of the cytochromes P450 that process xenobiotics are located within the endoplasmic reticulum. The membrane phospholipids to which the enzymes are anchored... 

As discussed earlier, Pgp, MRPl, and BGRP are expressed in normal tissues and are thought to be important for protecting normal cells from the accumulation of xenobiotics. The tissue distribution of MRPl is the most ubiquitous and is expressed in most tissues with high... 

Monoamine oxidase (MAO) is an enzyme present in the outer mitochondrial membrane of neuronal and non-neuronal cells. Two isoforms of MAO exist MAO-A and MAO-B. The MAO enzymes are responsible for the oxidative deamination of endogenous and xenobiotic amines, and have different substrate preferences, inhibitor specificities, and tissue distributions. MAO inhibition allows endogenous and exogenous substrates to accumulate, and may thereby alter the dynamics of regular monoamine transmitters, such as norepinephrine, serotonin, and dopamine. Specifically, MAO-A deaminates serotonin, norepinephrine, and dopamine, and MAO-B deaminates dopamine, [3-phenylethylamine, and benzylamine. In the human brain, about 75% of MAO is of the B subtype. Hence, the primary effect of MAO inhibitors (MAOIs) is to increase the availability of these neurotransmitters at the nerve terminal. 

Tables 3.1 and 3.2 define the nomenclature for these two major families and contain information on endogenous substrates and tissue distribution. Tables 3.3 and 3.4 contain information on drugs and other xenobiotic substrates, inhibitors, and inducers.

It is known that both the metabolism and the biological effects of 2-APA drugs can be modulated by other xenobiotics that influence the pool of free CoA or the activity of the CoA-dependent enzymes. Clofibrate and possibly other clofibric acid derivatives can increase the expression of long-chain acyl-CoA synthase and increase ibuprofen incorporation and tissue distribution into hybrid lipids in rats and humans [27,56-59]. The addition of valproic acid and pivalic acid, a metabolite of pivampicillin, to suspensions of isolated rat hepatocytes can also interfere with CoA pools and inhibit the formation of ibuprofenoyl-CoA reaction [60,61]. 

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