Xenobiotics metabolic activation

To date, there is very little known about if and how phytochemicals modulate the metabolism of GIT tissues other than the liver. Of particular interest are the xenobiotic metabolizing enzymes of the GIT, which are involved with transformation of drugs and toxins. Whereas the metabolic activities of the resident microflora dominate in the large intestine, mucosal enzyme activities are more important in the small intestine where bacterial densities are lower and the villi and microvilli increase the area of exposure. 

Minchin, R.F. and Boyd, M.R. (1983). Localization of metabolic activation and deactivation systems in the lung. Significance to the pulmonary toxicity of xenobiotics. Ann. Rev. Pharmacol. Toxicol. 23, 217-238. 

Fortuitous or co-metabolic biodegradation may account for a significant portion of the removal of xenobiotics in the environment.24 Numerous examples of co-metabolic activity have been described for pure substrates,22 but co-metabolism has been very difficult to demonstrate in mixed-substrate, mixed-culture systems, because products of the co-metabolic reactions of one species may be degraded by another.24 To encourage co-metabolism, easily degradable co-substrates should be included in the leachate prior to biological treatment. Fatty acids, which often occur in landfill leachates, may fulfill this requirement. 

O. mykiss 10 After 14 days, no adverse effects on survival, growth, or liver xenobiotic metabolizing activities 16... 

CYP450 antibodies leading to autoimmune hepatitis [68,69], Metabolic activation can also occur within the monocyte/macrophage and has been reported for many of the same xenobiotics (e.g., hydralazine) suggesting multiple mechanisms for xenobiotic autoimmune potential [68],... 

In Vitro Metabolic Activation. The target cells for in vitro mutagenicity tests often possess a limited (often overlooked) capacity for endogenous metabolism of xenobiotics. However, to simulate the complexity of metabolic events that occur in the whole animal, there is a critical need to supplement this activity. 

Induction of P-450 Metabolism and Isoenzymes. When organisms are exposed to certain xenobiotics their ability to metabolize a variety of chemicals is increased. This phenomenon can produce either a transitory reduction in the toxicity of a drug or an increase (if the metabolite is the more toxic species). However, this may not be the case with compounds that require metabolic activation. The exact toxicological outcome of such increased metabolism is dependent on the specific xenobiotic and its specific metabolic pathway. Since the outcome of a xenobiotic exposure can depend on the balance between those reactions that represent detoxication and those... 

The CYP family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. If a drug is to be orally active, it should be both chemically and metabolically stable. Metabolism normally only takes place at a specific position of a molecular skeleton and, unfortunately, metabolic regularities are exceptions. Experienced chemists also find it very difficult to predict where metabolism occurs in a molecule [1]. 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

Sipes IG, Wiersma DA, Armstrong DJ. 1986a. The role of glutathione in the toxicity of xenobiotic compounds Metabolic activation of 1,2-dibromoethane by glutathione. Adv Exp Med Biol 197 457-467. 

Van Bladeren PJ. 1983. Metabolic activation of xenobiotics Ethylene dibromide and structural analogs. J Am Coll Toxicol 2(3) 73-83. 

Hydrogen peroxide supports hepatocyte P450 catalysed xenobiotic/drug metabolic activation to form cytotoxic reactive intermediates. Adv Exp Med Biol 500 233-236. 

Enzyme levels and activities within the human population can vary considerably and many of the enzymes involved in the metabolism of xenobiotics are polymorphicaUy distributed in the human population. Genetic polymorphism (from Greek poly many , morph form ) is defined as the occurrence of at least two different alleles, with allele frequencies exceeding 1% at a particular locus. The allelic variants include point mutations as well as deletions and insertions and genetic polymorphism may cause an increase, a decrease, or no change in enzymatic activity. 

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