Aging Aging

Xenobiotic-Metabolizing Enzymes 121these intermediates interact covalently with vital cellular components, leadingto the manifestation of toxicity (2,3). For example, most chemical carcinogensare metabolized to reactive species that interact with DNA to inducemutations that may lead to the formation of tumors. Generally, the activationpathways are usually minor routes of metabolism and the body is wellequipped to deal with the limited amounts of reactive intermediates that areproduced. This defense mechanism proceeds through conjugation of the reactiveintermediates with the endogenous tripeptide glutathione, the glutathioneconjugates being excreted in the urine and feces following additional processingthat occurs principally in the kidney and intestine. It is therefore notsurprising that the cellular concentration of glutathione in the hepatocyte, themajor site of the bioactivation of chemicals, is high (about 10 mM). Depletionof the tissue stores of glutathione, whether by chemicals or as a consequenceof poor nutrition, can potentiate markedly chemical toxicity. The toxicity ofthe mild analgesic and antipyretic drug paracetamol (acetaminophen) is markedlyexacerbated if the animals have been depleted of glutathione as a resultof inadequate nutrition (4).It is evident that a chemical is subject to metabolism through a number ofpathways, most of which will result in deactivation. Certain routes of metabolism,however, will produce deleterious intermediates that are themselves subjectto deactivation through metabolism. Clearly, the amount of reactiveintermediates available for interaction with cellular components, and hence thedegree of toxicity, is largely dependent on the competing pathways of activationand deactivation. If an animal species favors the activation pathways of achemical it will be susceptible to its toxicity whereas if deactivation is favoredit will be resistant. 2-Aceylaminofluorene is a carcinogen that undergoesN-hydroxylation to generate the reactive, carcinogenic intermediates. Theguinea pig is unable to catalyze this reaction and consequently it is very resistantto the carcinogenicity of this chemical (5). Clearly, toxicity is not simply aconsequence of the intrinsic molecular structure and physicochemical propertiesof the chemical, but is also largely dependent on the nature and level of theenzymes present in the living organism at the time of exposure. Normally, theactivation pathway is a minor route of metabolism, but under certain circumstancesit may assume greater importance. Such a situation arises when thedeactivation pathways are saturated, as a result of intake of high doses of thechemical or when the activation pathway is selectively induced, for example,as a result of prior exposure to chemicals. Under such circumstances, the productionof reactive intermediates is stimulated, overwhelming the deactivationpathways, making an interaction with cellular constituents, and the ensuingtoxicity, more likely. Paracetamol is a very safe drug, the activation pathwaybeing a very minor metabolic route. In alcoholics, as a result of alcohol intake,