Tissue-specific metabolic pathways

Comparison of mutations in lung and bladder cancers of smokers reveals that the same complex mixture, tobacco smoke, can induce different types of mutations in different tissues. Differences in exposure routes, tissue-specific metabolic pathways, and distribution of exposure components and their metabolites are expected to account for dissimilarities. DNA adduct measurements in various tissues following exposure to tobacco smoke or smoke condensate indicate there are shifts in the predominant tobacco smoke-derived DNA damaging agents in various organs. 

Measurement of exposure can be made by determining levels of toxic chemicals in human serum or tissue if the chemicals of concern persist in tissue or if the exposure is recent. For most situations, neither of these conditions is met. As a result, most assessments of exposure depend primarily on chemical measurements in environmental media coupled with semi-quantitative assessments of environmental pathways. However, when measurements in human tissue are possible, valuable exposure information can be obtained, subject to the same limitations cited above for environmental measurement methodology. Interpretation of tissue concentration data is dependent on knowledge of the absorption, excretion, metabolism, and tissue specificity characteristics for the chemical under study. The toxic hazard posed by a particular chemical will depend critically upon the concentration achieved at particular target organ sites. This, in turn, depends upon rates of absorption, transport, and metabolic alteration. Metabolic alterations can involve either partial inactivation of toxic material or conversion to chemicals with increased or differing toxic properties. 

Function Tissue specificity (e.g., transport characteristics, metabolic pathways) Mechanisms of injury... 

The half-life of 2-hexanone and its metabolites in blood plasma has not been established however, elimination from the body does appear to occur in less than 24 hours following both inhalation and ingestion exposures (DiVincenzo et al. 1977, 1978). 2-Hexanone is not known to accumulate over time in any tissues in the body (see section 2.3.4). While elimination enhancement through stimulation of metabolism of 2-hexanone may reduce some forms of toxicity, if used within the short time that 2-hexanone is retained in the body, there is the risk that these same metabolic reactions may form reactive metabolites such as 2,5-hexanedione. Furthermore, concurrent exposures to other substances may also occur for which stimulation of these same metabolic pathways is contraindicated. Therefore, the benefit of stimulating specific metabolic pathways to enhance 2-hexanone elimination is unclear and should be studied further. 

Whole plasma can also be fractionated into specific lipoprotein size classes to further resolve the underlying biochemistry and metabolism of tissues that deliver these lipids to blood and selectively remove them. Thus, TrueMass analysis can be used to measure the lipid profiles of very-low-density lipoprotein, quantify the lipid pathways responsible for metabolic changes in the liver and measure profiles of high-density lipoprotein to quantify the flux of lipids in reverse cholesterol transport. 

The major metabolic pathways for tea catechins include glucuronidation, sulfation, and methylation. There are species and tissue-specific differences in... 

Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa. Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities. Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved. Specific examples of these types of interactions are given later in this section. 

The examples discussed here show that for two secondary metabolite pathways, metabolic engineering using transcription factors was successful. Modification of the phenylpropanoid/flavonoid pathway made use of the tissue-specific MYB... 

Tryptophan dioxygenase (Section 8.3.2) is only found in the liver other tissues have an indoleamine dioxygenase, with lower specificity, that catalyzes the same reaction. However, the pathway for onward metabolism of kynure-nine is found only in liver and mononuclear phagocytes, and induction of indoleamine dioxygenase by cytokines, such as interferon-y, leads to increased circulating concentrations and urinary excretion of kynurenine, with litde or... 

Research demonstrated that CLA isomers reduce body fat in growing animals (29-31) and its actions on fat and energy metabolism may, in part, be directed through changes in both PPARa and PPARy (32, 33). In addition, specific effects of CLA isomers on activity and expression of enzymes associated with anabohc pathways of lipid metabolism are reported (34). Eor example, CLA was observed to decrease the mRNA level of the A9-desaturase enzyme in both liver tissue and hepatocyte cultures (35). 

Hormone control of metabolism is regulated by chemical messengers secreted into the blood by different endocrine glands. These messengers, called hormones, travel to other tissues or organs, where they may stimulate or inhibit specific metabolic pathways. 

---