Xenobiotics, metabolism toxic

Yang CS, Brady JF, Hong JY Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity. FASEB J 1992 6 737. 

Studies on rats had shown no toxicity of astaxanthin preparations. Dietary administration of astaxanthin has proved to significantly inhibit carcinogenesis in the mouse urinary bladder, rat oral cavity, and rat colon. In addition, it is reported to induce xenobiotic-metabolizing enzymes in rat liver. 

Holme, J. (1985). Xenobiotic metabolism and toxicity in primary monolayer cultures of... 

L. W. Wormhoudt, J. N. Commandeur, N. P. Vermeulen, Genetic Polymorphisms of Human V-Acetyltransferase, Cytochrome P450, Glutathione 5-Transferase, and Epoxide Hydrolase Enzymes Relevance to Xenobiotic Metabolism and Toxicity , Crit. Rev. Toxicol. 1999, 29, 59 - 124. 

NRC 1993 Vieira et al. 1996). Whether differences in xenobiotic metabolism make the child more or less suseeptible also depends on whether the relevant enzymes are involved in activation of the parent compound to its toxic form or in detoxification. There may also be differences in excretion, particularly in the newborn who has a low glomerular filtration rate and has not developed efficient tubular secretion and resorption capacities (Altman and Dittmer 1974 NRC 1993 West et al. 1948). Children and adults may differ in their capacity to repair damage Irom chemical insults. Children also have a longer lifetime in which to express damage Irom chemicals this potential is particularly relevant to cancer. 

It is also common in discussions of xenobiotic metabolism to find that there is an assumption that all xenobiotics must be toxic and that any metabolism of the xenobiotic must reduce the toxic load. Of course the reality is that most xenobiotics (other than drugs) will possess no significant biomolecular activity (for reasons discussed in Chapter 5) and the degradation of a substance creates one or more new compounds that are equally likely to possess significant biomolecular activity hence degradation is no guarantee of detoxification. ... 

Caldwell, J. (1992) Problems and opportunities in toxicity testing arising from species differences in xenobiotic metabolism. Toxicol. Lett., 64/65, 651-659 Caldwell, J., Anthony, A., Cotgreave, I.A. Sangster, S.A., Sutton, J.D., Bernard, B.K. Ford, R.A. (1985) Influence of dose and sex on the disposition and hepatic effects of cinnamyl anthranilate in the B6C3F1 mouse. Food chem. Toxicol., 23, 559-566 Cattley, R.C., DeLuca, J., Elcombe, C., Fenner-Crisp, R, Lake, B.G, Marsman, D.S., Pastoor,... 

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. 

The magnitude of diazinon toxicity, like the toxicity of any xenobiotic, is affected by the rate of its metabolic biotransformation to both more and less toxic substances (Klaassen et al. 1986). Therefore, low xenobiotic metabolizing activity could result in greater toxicity. The newborn of several animal species, including humans, have a reduced ability to metabolize xenobiotics and may be more sensitive to diazinon toxicity. 

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. 

Metabolism often plays a central role in the efficacy of a drug and/or the toxicity associated with exposure to a drug or other xenobiotics. Metabolism may convert a prodrug to the pharmacologically active form, and may be a primary determinant of peak plasma concentration and half-life. Alternatively, competition for metabolism may be the mechanism for a drug-drug interaction. 

The major advantage of an in vitro system is that it represents a simplified system which allows the experimenter to address questions which cannot be tested in vivo. These systems can allow analysis of activation or metabolism at the single enzyme level. They can test proposed pathways of metabolism or activation. Such studies are not practical with in vivo systems. The major disadvantage is that in vitro systems are a simplified system and the results can be easily over-interpreted. In vitro systems cannot model the pharmacokinetics or toxicokinetics of xenobiotic exposure in vivo. In addition, there may be other, unappreciated enzymes or factors which influence metabolism/toxicity in vivo which are not present in the in vitro system. 

Ding X, Kaminsky LS. Human extrahepatic cytochromes P450 function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol 2003 43 149-173. 

Hengstler JG, Oesch F. Interspecies differences in xenobiotic metabolizing enzymes and their importance for inter species extrapolation of toxicity. In Ballantyne B, Marrs TC, Syversen T, eds. General and Applied Toxicology. Vol. 1. London Macmillan, 2000. 

The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone but are, by virtue of their ability to inhibit xenobiotic-metabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds. 

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