Enzymes induction, toxicological

Tacchi-Bedford, A.M., Whyman, G.D. McLean, A.E.M. (1988) DNA alkylation by 1,2-dimethylhydrazine in the rat large intestine and liver influence of diet and enzyme induction. Toxicology, 50, 181-191... 

Toxicological studies have demonstrated that there are no important problems with fluconazole. Therapeutic doses of fluconazole may cause enzyme induction in the Hver. This suggests that interactions with other dmgs cannot be excluded. The side effects are similar to those of itraconazole and include nausea, headache, and vertigo. Occasionally, increased Hver enzymes may be noted. Like itraconazole, fluconazole is contraindicated during pregnancy. 

The study of absorption, distribution, metabolism and excretion in toxicology studies, usually referred to as toxicokinetics, provides extremely useful information on the pharmacokinetics of high doses and of repeated doses of the compound. The dose dependency of the pharmacokinetics and the possible time effects, e.g. a decrease in exposure over time as a result of enzyme induction, is essential information for the interpretation of the toxicity findings as well as for the planned clinical studies. 

Enzymes are extremely important because they must function properly to enable essential metabolic processes to occur in cells. Substances that interfere with the proper action of enzymes obviously have the potential to be toxic. Many xenobiotics that adversely affect enzymes are enzyme inhibitors, which slow down or stop enzymes from performing their normal functions as biochemical catalysts. Stimulation of the body to make enzymes that serve particular purposes, a process called enzyme induction, is also important in toxicology. 

D.V. Parke, The effects of nutrition and enzyme induction in toxicology. World Rev. Nutr. Dietetics 29 96, 1978. 

Snyder, R. (2000) Profiles in toxicology microsomal enzyme induction. Toxicol. Sci. 55 233-234. 

In the safety pharmacology protocol, the interaction of multiple endocrine systems in test animals is addressed. As discussed by Harvey (1996) and by Harvey and Everett (2003), effects on adrenocortical function are frequently found in toxicology studies, sometimes related to enzyme induction and effects on steroid biosynthesis (Loose et al. 1983, Nebert and Russell 2002, Weber et al. 1993). Test procedures in animals are required when there is a reason for concern. Frequently however the effects observed are due to stress rather than specific interaction with the target organ, and may involve effects on catecholamine release from the adrenal medulla (Tucker 1996). Recently, much new evidence has been accumulated from the testing of industrial chemicals with effects on adrenal steroid biosynthesis (Harvey and Johnson 2002). 

Park, B.K. Kitteringham, N.R. (1990) Assessment of enzyme induction and enzyme inhibition in humans toxicological implications. Xenobiotica, 20, 1171-1185. 

Enzyme induction can have a significant impact on the resultant toxicological profile of animals dosed at high levels over the prolonged periods required for... 

Amacher, D. A., S. J. Schomaker, and J. E. Burkhardt. 1998. The relationship among microsomal enzyme induction, liver weight and histological change in rat toxicology studies. Food and Chemical Toxicology 36 831-839. 

Hood, A., M. L. Allen, Y. Liu, J. Liu, and C. D. Klaassen. 2003. Induction of T(4) UDP-GT activity, serum thyroid stimulating hormone, and thyroid follicular cell proliferation in mice treated with microsomal enzyme inducers. Toxicology and Applied Pharmacology 188 6-13. 

Talalay P, Fahey JW, Holtzclaw WD, Prestera T, Zhang Y. Chemoprotection against cancer by phase 2 enzyme induction. Proceedings of the VII International Congress of Toxicology. WA Seattie, 1995. 

Enzyme induction mediated by the AHR has both metabolic and toxicological consequences as outlined above and depicted in Fig. 8. However, a major complexity in examining AHR-mediated toxicity is that induction of phase I and phase II enzymes regulated by the AHR does not account for the toxicity of xenobiotic substrates that do not form reactive metabolites, such as TCDD. It is the parent compound, working through the AHR, that is toxic. 

During the last decade much attention has been paid to the toxicology of PCBs, particularly to the congeners that show the same type of toxicity as polychlorinated dibenzo-p-dioxines (PCDDs) and di-benzofurans (PCDFs). Certain PCBs, which lack chlorine substituents in the orf/>o-position, show a particularly high dioxin-like toxicity (enzyme induction through binding of CB to the Ah-receptor),... 

Enzyme Induction is extremely important in evaluating pharmacological, toxicological, and therapeutic activity of a drug since it affects the duration and intensity of drug action. 

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