Chemical and Physiological In uences on Xenobiotic Metabolism in Visual Studio .NET

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Chemical and Physiological In uences on Xenobiotic Metabolism
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RANDY L. ROSE and ERNEST HODGSON
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INTRODUCTION
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The metabolism of toxicants and their overall toxicity can be modi ed by many factors both extrinsic and intrinsic to the normal functioning of the organism. It is entirely possible that many changes in toxicity are due to changes in metabolism, because most sequences of events that lead to overt toxicity involve activation and/or detoxication of the parent compound. In many cases the chain of cause and effect is not clear, due to the dif culty of relating single events measured in vitro to the complex and interrelated effects that occur in vivo. This relationship between in vitro and in vivo studies is important and is discussed in connection with enzymatic inhibition and induction (see Section 9.5). It is important to note that the chemical, nutritional, physiological, and other effects noted herein have been described primarily from experiments carried out on experimental animals. These studies indicate that similar effects may occur in humans or other animals, but not that they must occur or that they occur at the same magnitude in all species if they occur at all.
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NUTRITIONAL EFFECTS
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Many nutritional effects on xenobiotic metabolism have been noted, but the information is scattered and often appears contradictory. This is one of the most important of several neglected areas of toxicology. This section is concerned only with the effects of nutritional constituents of the diet; the effects of other xenobiotics in the diet are discussed under chemical effects (see Section 9.5).
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9.2.1 Protein
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Low-protein diets generally decrease monooxygenase activity in rat liver microsomes, and gender and substrate differences may be seen in the effect. For example, aminopyrine N -demethylation, hexobarbital hydroxylation, and aniline hydroxylation are all
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A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Copyright 2004 John Wiley & Sons, Inc.
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CHEMICAL AND PHYSIOLOGICAL INFLUENCES ON XENOBIOTIC METABOLISM
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decreased, but the effect on the rst two is greater in males than in females. In the third case, aniline hydroxylation, the reduction in males is equal to that in females. Tissue differences may also be seen. These changes are presumably related to the reductions in the levels of cytochrome P450 and NADPH-cytochrome P450 reductase that are also noted. One might speculate that the gender and other variations are due to differential effects on P450 isozymes. Even though enzyme levels are reduced by low-protein diets, they can still be induced to some extent by compounds such as phenobarbital. Such changes may also be re ected in changes in toxicity. Changes in the level of azoreductase activity in rat liver brought about by a low-protein diet are re ected in an increased severity in the carcinogenic effect of dimethylaminoazobenzene. The liver carcinogen dimethylnitrosamine, which must be activated metabolically, is almost without effect in protein-de cient rats. Strychnine, which is detoxi ed by microsomal monooxygenase action, is more toxic to animals on low-protein diets, whereas octamethylpyrophosphoramide, carbon tetrachloride, and heptachlor, which are activated by monooxygenases, are less toxic. Phase II reactions may also be affected by dietary protein levels. Chloramphenicol glucuronidation is reduced in protein-de cient guinea pigs, although no effect is seen on sulfotransferase activity in protein-de cient rats.
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9.2.2 Carbohydrates
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High dietary carbohydrate levels in the rat tend to have much the same effect as low dietary protein, decreasing such activities as aminopyrine N -demethylase, pentobarbital hydroxylation, and p-nitrobenzoic acid reduction along with a concomitant decrease in the enzymes of the cytochrome P450 monooxygenase system. Because rats tend to regulate total caloric intake, this may actually re ect low-protein intake. In humans it has been demonstrated that increasing the ratio of protein to carbohydrate in the diet stimulates oxidation of antipyrine and theophylline, while changing the ratio of fat to carbohydrate had no effect. In related studies, humans fed charcoal-broiled beef (food high in polycyclic hydrocarbon content) for several days had signi cantly enhanced activities of CYPs 1A1 and 1A2, resulting in enhanced metabolism of phenacetin, theophylline, and antipyrine. Studies of this nature indicate that there is signi cant interindividual variability in these observed responses.
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