Susceptibility To Environmental Toxins

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A number of gene families determine the individual cellular settings of detoxifying enzymes and a person's capacity for enzymatic detoxification (see Chapter 7). This accounts for both an individual's susceptibility to environmental toxins and a predisposition for the development of environment-related diseases. The human super gene family of uridine 5'-diphosphate glucuronyl-transferases (UGT) is known to represent Phase II detoxifying enzymes that glucuronidate not only dietary by-products and endogenous metabolites, but also therapeutic drugs or polycyclic hydrocarbons and heterocyclic amines, which are known mutagens. The consequence of an impaired Phase II metabolism is an accumulation of cyto-and genotoxic xenobiotics that are generated by an adduct reaction with continuously produced reactive oxygen species from oxidative Phase I metabolic enzymes. The UGT1A7 gene encodes one specific UGT isoform that has been shown to glucuronidate several known carcinogens, including those from tobacco smoke. Transcripts of UGT1A are predominant in pancreatic tissue. Here the low detoxification activity of a specific UGT1A7*3 allele may represent a genetic risk factor and confer a predisposition for environmentally induced pancreatic injuries. In a genetic analysis of UGT1A polymorphisms in patients with pancreatic diseases by Ockenga et al.,2 the UGT1A*3 allele was found to be associated with pancreatic carcinoma, but also with a subgroup of patients with chronic alcoholic pancreatitis, of which 89% were also smokers. Although the presence and relevance of certain UGT1A polymorphisms is presently being disputed (unpublished observations) the reported data would strongly support the concept that acute and chronic pancreatitis can result from a complex interaction of genetic and environmental factors.

The pathologic effects of alcohol on the pancreas are difficult to study in humans. Ethanol and its metabolites, however, appear to have complex short-term and long-term effects on acinar cell physiology, to cause damage to cell membranes, and to affect cellular signaling pathways (see Chapter 6 and Chapter 14). Animal models, which have been frequently used to investigate the effect of ethanol in vivo, have demonstrated that the pancreatic injury induced by ethanol exposure is likely to be multi-factorial. The mechanism seems to include some degree of ductal hypertension, decreased pancreatic blood flow, oxidative stress, direct acinar cell toxicity, changes in protein synthesis, an enhanced inflammatory response, or the stimulation of fibrosis. Acute administration of alcohol in the rat results in increased injury during pancreatitis induced by a combination of pancreatic duct obstruction and hormonal hyperstimulation. Rats under chronic ethanol feeding had also more severe pancreatitis. Although the generation of oxygen free radicals has been clearly demonstrated in the pancreas of rats under continuous ethanol feeding, ethanol alone (i.e., without an additional disease-inducing stimulus) does not cause pancreatitis. Generation of free radicals has been shown to cause depletion of intracellular antioxidants, such as glutathione, and accounts for subsequent oxidant damage of lipids, proteins, and nucleic acids. Therefore, some of the toxic effects of ethanol may be secondary to its effect on lipid metabolism and other metabolic pathways. The genetic predisposition toward environmental toxins including ethanol is therefore likely to involve one or several of the genes that regulate cellular detoxification but also those that control intracellular processes targeted by toxin-induced physiologic and metabolic changes.

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Home Detox

Home Detox

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