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When our from the cycad nut, which is used extensively among residents of South Paci c Islands, is fed to rats, it leads to cancers of the liver, kidney, and digestive tract. The active compound in cycasin is the -glucoside of methylazoxymethanol (Figure 8.7). If this compound is injected intraperitoneally rather than given orally, or if the compound is fed to germ-free rats, no tumors occur. Intestinal micro ora possess the necessary enzyme, -glucosidase, to form the active compound methylazoxymethanol, which is then absorbed into the body. The parent compound, cycasin, is carcinogenic only if administered orally because -glucosidases are not present in mammalian tissues but are present in the gut. However, it can be demonstrated that the metabolite, methylazoxymethanol, will lead to tumors in both normal and germ-free animals regardless of the route of administration.
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b-Glucosidase
O NCH2-b-glucoside CH3N NCH2OH
CH3N
(gut microflora)
Cycasin [Methylazoxymethanol glucoside]
Methylazoxymethanol
Figure 8.7 methanol.
Bioactivation of cycasin by intestinal micro ora to the carcinogen methylazoxy-
FUTURE DEVELOPMENTS
The current procedures for assessing safety and carcinogenic potential of chemicals using whole animal studies are expensive as well as becoming less socially acceptable. Moreover the scienti c validity of such tests for human risk assessment is also being questioned. Currently a battery of short-term mutagenicity tests are used extensively as early predictors of mutagenicity and possible carcinogenicity. Most of these systems use test organisms for example, bacteria that lack suitable enzyme systems to bioactivate chemicals, and therefore an exogenous activating system is used. Usually the postmitochondrial fraction from rat liver, containing both phase I and phase II enzymes, is used as the activating system. The critical question is, To what
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extent does this rat system represent the true in vivo situation, especially in humans If not this system, then what is the better alternative As some of the examples in this chapter illustrate, a chemical that is toxic or carcinogenic in one species or gender may be inactive in another, and this phenomenon is often related to the complement of enzymes, either activation or detoxication, expressed in the exposed organism. Another factor to consider is the ability of many foreign compounds to selectively induce the CYP enzymes involved in their metabolism, especially if this induction results in the activation of the compound. With molecular techniques now available, considerable progress is being made in de ning the enzyme and isozyme complements of human and laboratory species and understanding their mechanisms of control. Another area of active research is the use of in vitro expression systems to study the oxidation of foreign chemicals (e.g., bacteria containing genes for speci c human CYP isozymes). In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor af nities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species.
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Anders, M. W., W. Dekant, and S. Vamvakas, Glutathione-dependent toxicity. Xenobiotics 22: 1135 1145, 1992. Coughtrie, M. W. H., S. Sharp, K. Maxwell, and N. P. Innes. Biology and function of the reversible sulfation pathway catalysed by human sulfotransferases and sulfatases. ChemicoBiol. Interact. 109: 3 27, 1998. Gonzalez, F. J., and H. V. Gelboin. Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metabol. Rev. 26: 165 183, 1994. Guengerich, F. P. Bioactivation and detoxication of toxic and carcinogenic chemicals. Drug Metabol. Disp. 21: 1 6, 1993. Guengerich, F. P. Metabolic activation of carcinogens. Pharmac. Ther. 54: 17 61, 1992. Levi, P. E., and E. Hodgson. Reactive metabolites and toxicity. In Introduction to Biochemical Toxicology, 3rd ed., E. Hodgson and R. C. Smart, eds. New York: Wiley, 2001, pp. 199 220. Omiecinski, C. J., R. P. Remmel, and V. P. Hosagrahara. Concise review of the cytochrome P450s and their roles in toxicology. Toxicol. Sci. 48: 151 156, 1999. Rinaldi, R., E. Eliasson, S. Swedmark, and R. Morganstern. Reactive intermediates and the dynamics of glutathione transferases. Drug Metabol. Disp. 30: 1053 1058, 2002. Ritter, J. K. Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chemico-Biol. Interact. 129: 171 193, 2000. Vasiliou, V., A. Pappa, and D. R. Petersen. Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism. Chemico-Biol. Interact. 129: 1 19, 2000.