Xenobiotics, metabolism responses

The lowest dose effects of diuron are seen at 0.27 mg kg-1 per day. Almost all of the low-dose expression changes are related to genes involved with xenobiotic metabolism and transport, including cytochrome P450 enzymes and several transferases. These data indicate that the cells are responding appropriately to a potentially toxic xenobiotic. These effects are widespread across the set of chemicals tested in ToxCast, so it is of interest that 2,4-D does not trigger a similar xenobiotic metabolism response. 

Apart from monooxygenases, other enzymes concerned wih xenobiotic metabolism may also be induced. Some examples are given in Table 2.5. Induction of glucuronyl transferases is a common response and is associated with phenobarbital-type induction of CYP family 2. Glutathione transferase induction is also associated with this. A variety of compounds, including epoxides such as stilbene oxide and... 

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

Iscan, M., T. Coban, and B.C. Eke. 1992. Responses of hepatic xenobiotic metabolizing enzymes of mouse, rat and guinea-pig to nickel. Pharmacol. Toxicol. 71 434-442. 

Hektoen, H., A. Bernhoft, K. Ingebrigtsen, J.U. Skaare, and A. Goksoyr. 1994. Response of hepatic xenobiotic metabolizing enzymes in rainbow trout (Oncorhynchus mykiss) and cod (Gadus morhua) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). Aquat. Toxicol. 28 97-106. 

Skaare, J.U., E.G. Jensen, A. Goksoyr, and E. Egaas. 1991. Response of xenobiotic metabolizing enzymes of rainbow trout (Oncorhynchus mykiss) to the mono -ortho substituted polychlorinated PCB congener 2,3,4,4,5-pentachlorobiphenyl, PCB-118, detected by enzyme activities and immunochemical methods. Arch. Environ. Contam. Toxicol. 20 349-352. 

McFadden SA. 1996. Phenotypicvariation in xenobiotic metabolism and adverse environmental response Focus on sulfur-dependent detoxification pathways. Toxicology 111 43-65. 

Many xenobiotics, or chemicals that are foreign to the body, undergo metabolism. This type of metabolism is different from the metabolism of food nutrients necessary for production of energy to drive bodily functions. The purpose of xenobiotic metabolism is to convert active chemicals into inactive forms or convert inactive chemicals into active ones, and to transform chemicals into more water-soluble forms so that they can be more easily excreted via the urine and bile. To understand drug action, it is important to know whether the original chemical or the product of its metabolism (its metabolites), or both, is responsible for the pharmacological effects. 

A recent paper clearly highlighted the limitations of in vitro systems in modeling whole-organism responses, which should be considered when developing biomarkers of in vivo toxicity. Dere and colleagues (58) compared the temporal gene expression profiles of Hepalclc mouse hepatoma cells and of the mice liver after treatment with a dioxin. The analysis revealed that Hepalclc cells were able to model the induction of xenobiotic metabolism in vivo. On the other hand, responses associated with cell cycle progression and proliferation were unique to the in vitro system, while lipid metabolism and immune responses were not replicated effectively in the Hepalclc cells. 

Ah receptor (AHR) A protein coded for by a gene of the Ah locus. The initial location of the Ah receptor is believed to be in the cytosol and, after binding to a ligand such as TCDD, is transported to the nucleus. Binding of aromatic hydrocarbons to the Ah receptor of mice is a prerequisite for the induction of many xenobiotic metabolizing enzymes, as well as for two responses to TCDD epidermal hyperplasia and thymic atrophy. Ah-responsive mice have a high-affinity receptor, whereas the Ah-nonresponsive mice have a low-affinity receptor. 

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